They had a biological model. They had multiple drugs that were showed activity against that model, and effectiveness in humans. Problem was, the model was wrong. Pharma’s burned billions chasing this as it’s possibly the biggest market imaginable.
Whether it was fraudulent or just incorrect is a different question. We don’t know all of the details of human biology. We don’t even know what all we don’t know. Most guesses work to some degree to keep pharma alive - otherwise nobody would fund the business.
Edit: Google the in the pipeline blog. This and other have discussed this at length.
I thought despite the fraud, it's still the best model we have[1]? The fact there was fraud doesn't mean the model is immediately incorrect. At best, it means its foundations are shakier than we thought, but it's not a slam dunk repudiation.
> It's much like climate science today: any dissent at all, even just questioning the predictions of catastrophe, immediately brands you as a heretic.
I'm not sure I understand this. We've added hundreds of gigatons of carbon to the atmosphere. There's no mystery here, it's basic physics and chemistry that this will change things, and it's accepted that we don't know exactly _how_ things will change. The alternative: "adding gigatons of carbon to the atmosphere will _not_ change anything" is simply non-sensical. It goes against the basic rules of physics and causality. I'm happy to be proved wrong here, I just legitimately can't see how an alternative position makes any sense.
Edit: I see you specifically pointed out "predictions of catastrophe", which if that is true (and not just the position of radicals on Twitter) is indeed unfortunate.
Yes, there is overwhelming evidence of climate change. And that we are causing it.
However research into what we humans can do to ameliorate it is verboten. For example https://www.scientificamerican.com/article/fertilizing-ocean... was an actual experiment that found a low cost way to both remove lots of CO2, and improve a fishery. But that line of research has been shut down.
Likewise research into the current impact is only allowed if it agrees with what is politically correct. For example many researchers have found that current severe California forest fires are mostly due to poor past policies, that have resulted in very dense forest, with a large fuel overload. But research that stresses the impact of climate change are easier to publish, and this shifts the apparent consensus on the causes of things like the major 2025 fires in the Los Angeles area.
> The project is also unlikely to bury much if any carbon dioxide for one simple reason: metabolism. As other iron fertilization experiments have shown, it is relatively easy to get plankton to bloom, but it is harder for that bloom to sink to the bottom of the ocean, where it takes CO2 with it.
Do you really think that adding iron releases net carbon? That would be hard to explain chemically.
The worst case scenario laid out in that article is that most of the carbon absorbed, was later rereleased. So net zero carbon, not net carbon emitter.
I've seen other reports of that exact experiment that estimated a significant net carbon sink. The actual experiment failed to make measurements that lets us know which actually happened.
Regardless, we've certainly demonstrated that, at least sometimes, there is significant net carbon capture, at low cost. Given the certainty of global damage at present, I believe that this justifies continued experimentation. Even if it means accepting possible risk to local ecosystems. The local ecosystem can generally recover. The planet, not so much.
You think the chemical compounds were just magiced into the ocean with no carbon intensity. It literally says carbon will not be absorbed and that geoengineering is not the goal.
> There are also money issues like with the alzheimer's situation. (that is: If climate change is dooming us then we should send more money to climate scientists)
Absolutely, the issues are similar
And if this can upend the business model of some big companies we'll give some "incentives" to some "doubtful" scientists even if their doubts are unfounded (actually very well founded but you get the gist)
Which sucks because such work should be free of pressures and incentives
> we should send more money to climate scientists.
Couldn't disagree more.
Please spend it on those who might actually fix something.
There's plenty of can remove carbon or can undo the effect of X on Y. Let's stop falling back on the bad argument of we must leave nature alone right after arguing we change billion dollar industries because we can.
We shouldn't learn to be custodians watching the planet die because of past mistakes, we should be fixing and improving the planet and improving on nature because we can, must and should, shoulder this reaponsibility.
Please not _yet more modelling_ burning HPC into the ground just for a crappy bar line graph (based on assumptions)...
> we should be fixing and improving the planet and improving on nature
How do you do this without a process of finding out what works and what doesn't? Isn't that science? Or am I misunderstanding you saying no more modeling to mean we already know everything we might need to know in order to shoulder this planet scale responsibility and just collectively aren't doing anything except making bar charts?
What does your proposal actually look like without science or climate modeling?
> If climate change is dooming us then we should send more money to climate scientists.
Depends! If you're a large fossil fuel company, the obvious move might be to spend more money on advertising agencies scientists, or entire foundations who question climate science instead.
I am baffled by the number of people on HN, presumably a website for and by technical people, who fail to consider secondary and tertiary effects when it fits their worldview to do so.
There is a yawning abyss of states in between extinction and 'boy sure is a few degrees warmer out here' and none of them are good.
Many organisms would benefit from a warmer climate, just not humans.
We rely on extremely narrow conditions for the fragile supply chains and power structures that keep us on the ragged edge of civilized to continue working. We had an extremely mild contagious disease outbreak, by historic standards, and our economy is still feeling the effects!
Imagine the impacts of something like wildly different rainfall patterns, increased rate of global infectious disease, shifted agricultural zones, changes to Jetstream patterns, large scale crop failures, loss of water supplies, temporary local ecosystem collapses etc. These changes are incredibly fast on the scale of what it takes to reach ecological equilibrium.
These of course mean nothing to biological life, writ large. Life will recover and adapt. To fragile human civilization they mean refugee crisis, resource wars, failed infrastructure, and ten thousand other existentially terrible things.
I get your point but on the other hand humans live quite well in places like Medicine Hat say where it swings from -40 C in winter to +40 C in summer. Against that the likely warming by say 2100 is I think 1.5C up from what it is today which might be just about noticeable?
Did you read the post at all? Second order effects, not primary effects. Its exasperating how much effort people will put into not understanding the smallest things when they are inconvenient to their worldview.
> There's no mystery here, it's basic physics and chemistry that this will change things, and it's accepted that we don't know exactly _how_ things will change. The alternative: "adding gigatons of carbon to the atmosphere will _not_ change anything" is simply non-sensical. It goes against the basic rules of physics and causality. I'm happy to be proved wrong here, I just legitimately can't see how an alternative position makes any sense.
With any position, you have to distinguish between its thoughtful advocates and its thoughtless ones-every position has both
Any thoughtful “climate change sceptic” is going to say (a) of course the climate is changing-it always has and always will; (b) of course it is implausible than human activity has literally zero impact on that change. But that still doesn’t tell us: (i) the relative scale of anthropogenic versus natural causal factors; (ii) the validity of any specific predictions of future change; (iii) the likely socioeconomic impacts of any future changes that may occur. It is totally possible that a person may affirm (a) and (b) while questioning the “consensus” on (i) and (ii) and (iii)
Personally, I don’t have a strong opinion on the substantive issue - but I wonder about the extent to which mainstream discourse on the topic represents good epistemic hygiene. It is even possible that the sceptics are on the whole more wrong than right, but simultaneously the mainstream response to them is more irrational than rational.
Yes I believe GP was focused on the catastrophe part. It's very likely correct that our CO2 emissions are warming the atmosphere ocean etc, but it's not clear that runaway warming is inevitable or that life or geology have feedback mechanisms that turn an exponential into an S curve. That is, after all, basically what natural selection tends to do. Turning the table again, even if there are corrective factors humans might have immense suffering before it stabilizes. So we don't know.
You didn't ask, but my opinion on it is that we'll probably stabilize on a cleaner energy source and find natural countermeasures when suffering ticks up. Any top down pressure to change things whole cloth seems doomed, no matter how benevolent. We're closed loop creatures.
For Climate Change it's a question of opportunity costs. With expected inputs how much will temperature change? What are the effects of that change? How much effort to you put into changing the inputs? How much effort do you put into dealing with the effects?
The biggest difference is that Climate Change is a deeply political question with a bit of science tossed in. Alzheimer's is the mirror opposite - it's a scientific question with politics added to the same degree of most other things.
> It's much like climate science today: any dissent at all, even just questioning the predictions of catastrophe, immediately brands you as a heretic.
I think this is not a great example, as there’s a huge group of people that, in fact, does not agree with the consensus and would happily fund research that (tries to) prove otherwise.
I fully agree with your point, though, just not the example.
The comment you were replying to was talking about funding. If you could develop a scientifically plausible model to defend the "burning fossil fuels is not so bad, actually" thesis, your funders would include the oil companies and the greater petrochemical industry. There is a lot more money to fund projects there than... anywhere else in the world, really, by a wide margin.
well oil companies funded "lead fuels are safe" research...
...and it really did backfire (in public relations, politics, etc)
now... I don't think they can actually fund 'research-for-their-profit' -- I mean, would you believe "petro is good for earth" research coming from oil companies, even after the 'lead is good or neutral' research?
Not uncritically, but if the research presents a logically consistent hypothesis, and evidence supporting it, then it would be worth following up on with independent groups and if it remains consistent to scrutiny then it should be accepted.
There are so many counterexamples proving that your statement is just not true. I'll give you just one example, the Berkeley physics professor Richard Muller that took funding from the Koch foundation to attempt to "prove" that the satellite temperature data was "miscalibrated" and estimates of actual warming were overblown. Started the project in 2010. First published in 2011 showing that in fact the warming was real and using more advanced calibration techniques actually showed the warming was worse than we thought.
Expecting scientific rigor is not a bad bias: everyone who has been willing to do actual science agrees that climate change is real and significant. For example, Richard Muller was a climate skeptic who had a great job at one of the most prestigious universities in the world, got funding to establish a team to critically review climate science research … and concluded it was right:
“When we began our study, we felt that skeptics had raised legitimate issues, and we didn’t know what we’d find. Our results turned out to be close to those published by prior groups. We think that means that those groups had truly been very careful in their work, despite their inability to convince some skeptics of that.”
If you haven’t read up on both, it’s hard to appreciate how unlike climate science is from the beta amyloid theory. The latter has some evidence but there were always alternate theories by serious researchers because it involved multiple systems which scientists were still working to understand and basic questions around causation and correlation had significant debate.
In contrast, climate scientists reached consensus about climate change four decades ago and by now have established many separate lines of evidence which all support what has been the consensus position. More importantly, since the 1970s they have been making predictions which were subsequently upheld by measured data from multiple sources. The ongoing research is in fine-tuning predictions, estimating efficacy of proposed interventions, etc. but nobody is seriously questioning the basic idea.
Almost all of the people you hear dismissing climate change are funded by a handful of companies like Exxon, whose own internal research showing climate change was a significant threat produced a chart in 1982 which has proven accurate:
having worked in amyloid, and in an a-beta lab in the second half of the 2000s, we always said under our breath in group meetings that we were skeptical about the amyloid hypothesis, but our grant applications certainly did not say that (or if they did it was a quick throwaway sentence). And I think the lab that I landed in was one of the most honest scientific labs in biochemistry/chemical biology.
Over the past decades the group that are not happy with the AGW consensus in the hard earth sciences crowd have principally funded FUD via think tanks, ala the pro-tobacco lobby back in the day, rather than research.
The few examples of research driven from the skeptic PoV (eg: urban heat skewing, etc) have landed on the side of the AGW consensus.
If anything the current consensus on the scientific front lines is that the alarmism is understated, and the real orthodoxy is astroturfed denial of the facts.
The global fossil industry is worth around $11 trillion a year. It supports some of the worst regimes in the world.
Of course they're going to try to FUD away the science, with the usual copy-paste narratives about how it's really scientists and academics who are corrupt.
It's all about money, power, and entitlement. Not about truth or responsibility.
But no amount of PR nonsense, astroturfing, and false accusation is going to make the slightest difference to climate reality.
Hah! What do you call the cap and trade group? The whole trillion dollar "carbon credit market" is a farce built to profit from climate change catastrophism.
You are mistaking the beneficiaries here. Carbon credit scheme is indeed a greenwashing scam and it is pushed by the oil and gas (plus adjacent) industries. It is plainly obvious that shuffling emissions between jurisdictions does jack shit against reducing the actual real amount of emissions to the atmosphere. Basically the main proponents of the carbon credit fraud are the same people financially motivated to reject long term climate change consequences (aka anti-"catastrophists" in your lingo).
If cap-and-trade held the same levels forever you would be correct. But all of the cap-and-trade systems I am aware of have a built-in lowering of the cap over time. So they start out doing nothing/very little, then ramp up to meaningful reductions over time.
The idea being both to make it easy to get people to agree today (the reductions are tomorrow's problem), and to allow time (and foresight) for industry to adapt to where things are going.
Small change compared to global fossil fuels. Energy (which is still mostly fossil fuels) is 10% of the world GDP.
Climate-change denial is just like tobacco-cancer denial. It's the same banal "I win, you all lose" mechanism. Enormous resources are available (along with the useful idiots) to propagate falsehoods.
>> It's much like climate science today: any dissent at all, even just questioning the predictions of catastrophe, immediately brands you as a heretic.
Nonsense. It is actually quite unlike climate science, where the consensus of catastrophe and the evidence for it are both overwhelming. Dissenters are listened to only to the extent they can provide overwhelming evidence to the contrary, which they so far cannot.
The problem is that the top researchers in the field have spent their lives devoted to amyloid beta. They may well have helped direct hundreds of millions in grants to this line of research.
The idea that they have blocked the treatment of Alzheimer's rather than helping it, is very, very painful. This is perfect for creating cognitive dissonance.
And so, no matter what the evidence, they remain committed to the conclusion.
As a result, the latest Alzheimer's drug to enter stage 3 FDA trials is Trontinemab. (It is currently in stage 3.) It targets the amyloid target.
A relative drop in the bucket is going to, say, the infection hypothesis. This despite the fact that the only intervention that has been shown to reduce the incidence of Alzheimer's, is the shingles vaccine.
Many in this thread, who have evidently spent very little time studying the topic, have confidently concluded the experts are wrong.
I, also a non-expert, spent six months studying what the experts are doing, concluded that they actually seem to know what they’re talking about, and shared my understanding of that with other non-experts.
If you’re going to dismiss me for saying the experts are right, since I’m
not an expert, then shouldn’t you dismiss those who spent far less time than I to learn about the subject, who are saying the experts are wrong?
Ha! You must be using a different username than I knew you by then. Hit me up on one of the many platforms we’re probably both on if you like, would be good to reconnect.
For you, simply listing the author of the post is enough to discard it. Not everyone is that well informed, so it would be helpful for you to add another sentence explaining why this author has no credibility with you.
By this logic, we wouldn't have some of the breakthroughs made throughout history. Outsiders have made some pretty interesting leaps (later honed by experts). Expertise is great, but it can exist outside of formal education, and it isn't the only metric.
"Amyloid plaques form one of the two defining features of Alzheimer’s disease, the other being neurofibrillary tangles"
Interesting that the latter is inside the neurons while the former is outside - speaking of complexity. The article also describes that activating microglia back helps with amyloid plaques while this
"The neurofibrillary tangles (NFT) and amyloid-ß plaques (AP) that comprise Alzheimer's disease (AD) neuropathology are associated with neurodegeneration and microglial activation. "
Human body reminds a large monolith codebase - fixing one thing breaks some other :). Claude Code, Human Body CRISPR edition, can't come soon enough...
>there is even easier way to estimate the chances of time wasting - it is a "rationalist" website, an "effective altruism"-like version of rationality.
Is that supposed to be an endorsement or a dismissal? The ostensible goals of "rationality" seem like good things, so it sounds like an endorsement, but in the wake of the FTX/SBF fallout they got a bad rap.
It is worse. The code changes are mostly random, only surviving the tests of fitness nature is applying (on various levels though; immediately catastrophic changes on level of cell biology are sorted out). And at least the high-level tests are also random and unreliable.
So basically it's a codebase mostly composed of bugs, and the features mysteriously work because they're based on bugs that happen to be mitigated by other bugs. :)
Many in the research community realised the model was wrong a long time ago. This is a great read about the reasons why: 'How not to study a disease: the story of Alzheimer’s.' by Karl Herrup.
The current findings seem consistent with "both plaques and tangles are significant components of the pathology" and "our interventions are typically late and the accumulated neurological damage is already extreme by the time clinical symptoms show".
Attacking the plaques wasn't completely worthless - findings show that this often slows disease progression, especially in early cases. There are pre-symptomatic trials ongoing that may clear the air on whether "intervention is late" is the main culprit in treatment underperformance.
It's a classic example of "correlation does not imply causation". It was indeed observed that some patients with neurodegenerative conditions do indeed have amyloid plaques. It was further observed that patients with known Alzheimer's do not necessarily have amyloid plaques and patients without it do have plaques. The existence of amyloid plaques itself or the level, apparently, correlates extremely poorly, if at all, with the existence, onset or severity of the disease. Drugs attacking amyloid plaques might work, but they don't reverse the disease and do very little to slow progression. That's all scientific observations.
> I thought despite the fraud, it's still the best model we have[1]?
It is observed that one of the features of neurodegenerative diseases is decline in glucose metabolism. Supplementing energy availability (e.g. ketones [1], creatine [2]) does improve symptoms in patients with wide variety of CNS diseases, including Alzheimer's, senile dementia, epilepsy, and migraines.
The ATN model you have linked might as well be just ONE OF possible pathways to glucose uptake inhibition, which could be the causal pathology of the symptoms.
So no, it is very much not necessarily the best model we have. Inhibiting any pathway towards a disease is always a good thing, but the characteristics of "best" models are broad applicability and we have a serious contender.
The Amyloid hypothesis persisted for so long because we didn't have any obvious counterarguments since it is so hard to do studies on the brain. Which also means that it's not a bad hypothesis.
What happened is we got the tools to start studying viral associations with other diseases and ... whooops ... suddenly there are associations. The shingles and RSV vaccines seem to affect dementia while others like influenza don't.
Now people can ask questions about why those particular vaccines affect dementia while others don't. And suddenly we have falsifiable tests.
Now we can subject all hypotheses (including Amyloid) to stronger scrutiny.
There were no cointerarguments? There was a very simple counterargument: where was the causal data? If none exist why should I counter argue when you hadn't proven it to begin with.
There is a LOT of causal data. Autopsies of brains of Alzheimer's patients were rife with amyloid. People with mutations that caused amyloid got Alzheimer's earlier than others.
The hypothesis didn't come from nowhere.
To contrast, look at how much trouble medicine has had treating brain tumors. It has taken a long time to get effective treatments for various reasons. And Alzheimer's is way less direct in cause/effect.
> People with mutations in those genes got a particular type of inherited alzheimers early, this says nothing about the cause of general Alzheimers.
This is completely analogous to claiming that people with mutations in BRCA (which causes a lot of early breast cancers) says nothing about general "cancer".
That's simply flat-out wrong. Genetic mutations like BRCA affect certain subsystems and many of those subsystems are common and relevant to many different cancers outside of breast cancer or breast cancers that appear later. Lots and lots of cancer research proceeded by studying the common systems that BRCA affects. Sure, those subsystems aren't involved in every cancer, but they're involved in a solid chunk of them.
And, even better, when you find one that isn't affected by one of those subsystems that BRCA touches, that's an interesting result, too. Now you can look at what the differences are, figure out what the new subsystems are and categorize your cancer more specifically which makes successful treatment more likely.
There is absolutely no reason to believe that Alzheimer's is any different on that front.
Correlation is not causation but it's a pretty good idea to start with how blindingly obvious differences in brains affected with the disease might be related with the disease. There's also evidence that it precedes the symptoms of the disease.
And it's also not a good idea to suppose that you are dealing with unrelated effects without good reason. Mutations->more amyloid->earlier symptoms should be considered indicative of the disease pathway until sufficient evidence counteracts that, by Occam's razor.
Im not gonna try to correct you because its probably going to be futile, but I implore you to paste this thread into chatgpt and ask where you could be wrong in your logic.
Correlation not causation is all the more important in a topic like this; nothing you said suggests amyloid causes alzheimers or just forms because of it.
What exactly do I need to say further? My first comment was that "scientists today still don't understand correlation =/= causation" and the replies are all scientists who try to explain again how correlation can still mean causation (no it doesn't, and it definitely doesn't in this case and that has been the root cause from the beginning). So I tried to implore you to go review your text yourself, but you are clearly above it, so not sure what else I could do here.
I would turn around the same request to you. I would ask that you look at how scientific research and hypotheses are actually created and the messy nature of evidence for anything that isn't particle physics and not just repeat cliches.
Research on the human body start with an observation, for the good reason that the omniscent orb has not invented yet, and what is causation and what is correlation is yet to be determined. Then, sometimes after years of research, it can be determined if what was observed was causation or correlation. That's why study that don't bring to a new discovery are extremely valuable nevertheless, as they show a path that was just a false lead and allow other researches to seek for something else
It is sad. That reply, which you rightfully were irritated by, could have been expressed as a polite question.
That sort of question is what the response from user @bsder above helpfully tries to answer. That mode would invite more productive discussion, not more defensive annoyance.
Rules on HN say “Be kind. Don't be snarky. Converse curiously; don't cross-examine. Edit out swipes.” but it is hard.
All I can suggest is: be patient and try to be positive
Ah causal data! It’s a shame none of the scientists or statisticians thought of getting causal data. How would we get that? Well maybe we could just inject amyloid into a person’s brain. Or simply remove all the amyloid from a person’s brain. That should do it, right?
I mean an amyloid injection is wildly unethical and it’s also not the natural progression of Alzheimer’s. Removing amyloid is a simple matter of investing billions of dollars into drug development. Also how do you tell whether that was actually “causal” if the patients improve after plaque removal.
I mean come on, you have to work the evidence and the experimental tools that we actually have. This kind of epistemic puritanism doesn’t help anyone.
An obvious counter hypothesis is the amyloid is produced to counter an infectious agent. It is a reaction to that, not the cause. I think HSV-1 has been hypothesised. I'm not that up on it, just saying there are alternatives.
Which is only relevant if you actually find an infectious agent doing something in the right place, which so far we have not.
The vaccine prevention connection for example AFAIK is just pure statistics: you get the shingles vaccine, your population level Alzheimer's risk drops but we have no direct evidence of why this should be.
Its entirely possible we later find it has no effect and it's a population level quirk of people who were likely to get a shingles vaccine until that research - conversely the cost of just getting one is incredibly low (hence why I did, in relation to that exact data).
I miss Derek Lowe's "Thing I Won't Work With" series. I know there have always been large gaps between those posts, but it's been seven years since the last one so I guess they might be over. An excerpt from a favourite of mine:
"But I have to admit, I'd never thought much about the next analog of hydrogen peroxide. Instead of having two oxygens in there, why not three: HOOOH? Indeed, why not? This is a general principle that can be extended to many other similar situations. Instead of being locked in a self-storage unit with two rabid wolverines, why not three? Instead of having two liters of pyridine poured down your trousers, why not three? And so on - it's a liberating thought. It's true that adding more oxygen-oxygen bonds to a compound will eventually liberate the tiles from your floor and your windows from their frames, but that comes with the territory."
Yeah; they had a wonderful earthiness to their language; both highly technical and highly vivid. Like this comment on hexanitroisowurtzitane:
> Recall that this is the compound whose cocrystal with TNT is actually less dangerous than the pure starting material itself, and yeah, I know that sounds like the guy at the pet store packing a starved Komodo dragon into the carrier with your new dog, just to calm him down some.
I'm guessing he just ran out of nasty chemicals. Either that, or he got tired of it and followed his muse elsewhere.
> Whether it was fraudulent or just incorrect is a different question.
And probably the more important question. How badly is the machine that does science broken? If we don’t focus here and fix it, there will be further decades without progress, all while wasting further billions.
> Whether it was fraudulent or just incorrect is a different question.
Sorry but good science should be reproducible an given the amount of major retractions around this field I think this starts to become more than a passing question.
Lots of work is built on top of the model which means a lot of money change hands and a lot of honesty hard work was done.
Those who built the bad model should be being asked why a) they were so wrong (bad conclusions are fine) b) their data was so bad (this is not defensible) c) they didn't push for reproducing their work sooner to support the field (more of a daming statement of a field which treats a statistical analysis as a push button tool)...
The peer review process was repeatedly cheated by self-serving fraud. The medical field requires honest results and reporting. Why are you defending the fraud?
Science is no longer a hobby for the idle rich, it's an occupation. Peer review cannot function in a hostile environment governed by self interest (results == resume). Science practice needs to adapt to modern conditions rather than to pretend the idealized system that worked for an exclusive and elite group would work for a competetive worldwide industry.
> Pharma’s burned billions chasing this as it’s possibly the biggest market imaginable.
To be clearer, Pharma is chasing a nice long treatment plan, that will require expensive drugs till the end. Pharma does not heal - this is not good for business. So there are criteria around what they are searching for.
> To be clearer, Pharma is chasing a nice long treatment plan, that will require expensive drugs till the end. Pharma does not heal - this is not good for business.
This is a trope regurgitated by people who don't know any better. It would imply that pharma are deliberately avoiding research directions that would generate cures, or (even worse) discovering cures and putting them in a dark secret safe somewhere.
The reality is that drug development is serendipitous and really hard, and any company seeing even a sniff of a drug that works will throw everything behind making that drug a success. During the early stages of investigation of a promising new agent, the animal data can't predict much, and certainly can't predict whether something is "curative" - this would only be seen during human trials, after which hiding that benefit would be close to impossible. It's just not how it works.
There are plenty of examples of actual (rather than functional) cures being developed and marketed:
1) Previously-untreated DLBCL (a type of blood cancer) can be cured. CHOP chemotherapy cured ~35-40% of cases. The addition of rituximab boosted that to 60-65%. There then followed a long string of failed phase III studies (probably billions spent, cumulatively) trying to beat rituximab + CHOP, and finally in recent years there has been some success. So: multiple attempts across multiple pharma companies, trying to improve on an already impressive cure rate... not much evidence of an anti-cure conspiracy.
2) Hepatitis C - cures were discovered and marketed from ~2014 onwards; now ~95% of cases can be cured with a treatment lasting only a couple of months. So: multiple treatments, from multiple pharma companies, which offer a hugely effective cure for a pretty unpleasant disease.
From the human perspective, researchers are people, and they do have their incentives. Making a breakthrough, of any kind, is important for them - even if for their career (but many do genuinely care and want to help humanity as a whole).
From marketing and sales perspective, look at what happen to pharma companies capitalization when Ozempic appeared: a relatively small Elly Lily suddenly got bigger then Merck, Novartis, Roche or Johnson & Johnson. You can hardly call it a long treatment plan with expensive drugs "till the end".
Really, there is a lot of bad things going on in healthcare and pharma industry, but the conspiracy theory "they don't want to invent efficient drugs" really makes no sense when you dig deeper.
I agree with you but Ozempic is a bad example here. Part of the reason it is so valuable is that patients usually must take it for the rest of their lives. Its actually the perfect example of “evil” pharma since patients slmost akways regain the weight if they stop taking it. This leads to dependence or people searching for grey market sources.
An example of “good” pharma would be Hepatitis C. We can now cure that. Although, pharma is charging the lifetime equivalent in order to do that (a treatment can run over $100k and insurance balks at covering it)
So pharma will absolutely develop a cure if they can. They however will still charge you as if you had to take a dose for the rest of your life.
> I agree with you but Ozempic is a bad example here. Part of the reason it is so valuable is that patients usually must take it for the rest of their lives. Its actually the perfect example of “evil” pharma since patients slmost akways regain the weight if they stop taking it. This leads to dependence or people searching for grey market sources.
Not really. Note that it's not taking ozempic for life vs taking nothing for life, but actually taking ozempic for life vs taking ozempic and 5 different medications for life when obesity related illnesses bite you in the ass. So generally ozempic still is "good" pharma (and the plot twist is that almost every pharma is good pharma!).
It's ridiculous to say that pharma is "evil" simply because it isn't a one time treatment, especially when you don't know if a one time treatment is even biologically possible. The water company isn't evil for failing to provide me a single glass of water that meets my lifetime hydration requirements.
> Part of the reason it is so valuable is that patients usually must take it for the rest of their lives.
Well yes, Ozempic doesn't solve the habits of a bad diet.
The weight rebound is surely due in little part to removal of hunger suppression as in "hormone rebound", but if you resume eating 5000+ kcal/day because you don't have something that keeps you from doing it, you'll end up in the same situation as before. Ozempic was never meant and is not going to fix your diet. That's a psychological and environmental problem.
Which illnesses have been cured? Diabetes, cancer?
> From the human perspective, researchers are people, and they do have their incentives. Making a breakthrough, of any kind, is important for them - even if for their career (but many do genuinely care and want to help humanity as a whole).
Researchers are people, but they are paid and directed. They can't go off and do what they like. The corporation directs them, and they are paid for their efforts. Researchers (and all working people) aren't doing what is right - they are doing what they are paid to do.
All the financial upside for pharmaceuticals is in prolonged treatments. It is a 'long sickness' industry. This is perhaps too bitter a pill to swallow for most, so this is where marketing and education come in with the sugar.
I've hung out with a lot of pharma folks, and the business is really complicated. Most of the companies aim to both help people and to make a lot of money, and will choose projects based on some balance of those -- sometimes in dubiously ethical ways (e.g. tweaking formulations of existing products to extend the patent) and sometimes in basically fine ways (e.g. lots of the improvements in diabetes management which have helped a ton of people; at least the targeting is fine here though often not the pricing). Obviously chronic diseases that affect lots of rich people are a prime target to make money, so drug companies make lots of drugs for these, and they usually aren't curative because chronic diseases are hard to cure (but see e.g. Hep C which is now curable). There are also companies with rich investors who want to cure death, or at least cure particular diseases that they fear or have a genetic predisposition to (lots of unethical behavior from a certain now-defunct company that tried to do this).
For cancer in particular, pharmas don't (and mostly can't) just target a drug to chronically treat some cancer over the long term but not cure it. Instead they pick some target that's believed to contribute to development (/ metastasis / treatment resistance / whatever) in whatever cancer, and make a drug to interfere with it or to target an immune response to cells that make it. If it's stable, nontoxic, and looks potentially effective enough they'll take it to clinical trials. During clinical trials they'll find out whether it does nothing, gives you a few extra months, or has a chance at curing the disease. Usually the answer is that it does nothing or almost nothing, or isn't worth the side effects, and then the company wasted its time and money. Drugs with a chance to cure common types of cancer can be enormous successes -- see eg Herceptin.
Cancers are difficult diseases and it's rare to find something that reliably cures them. But drug companies aren't pulling their punches. Like they would never say "oh this drug clears breast cancer too reliably, we should make it less effective so that people will be more likely to die but also might take it for longer".
But researchers are not necessarily paid by corporations, and governments, foundations, and such are generally more willing to hand out grants that forego short-term profitability for long-term gains. And while a company might not be interested investing in research that could undermine one of their core products, that obviously does not apply to competing companies that do not already have corresponding products. What better way to break into a market, than to render your competitors' products obsolete?
> Which illnesses have been cured? Diabetes, cancer?
Chicken pox, polio, hepatitis C, dracunculiasis, yaws, malaria (on the way of it), tuberculosis, syphilis, everything that can be killed with antibiotics, rubella...
Imagine your role is allocating spending on $10B/year of medical research and you are presented with two strategies: spend everything searching for the cure for one poorly understood condition, or allocate to treatments improving standard of care for 100 conditions.
Improving standard of care for 100 is less risky/more profitable because you have more shots at an expensive process with a high failure rate. And it is a lower bar to improve patient care than to permanently fix a medical mystery. But there is another factor. Focusing on treatment/management over cure most likely maximizes the positive impact on patients within the the constraints you work under.
There have been at least three new major treatments for a chronic thing I have that received FDA approval over my lifetime. Those treatments have had a massive impact on my quality of life, ability to have a career, etc. I don't believe that happens for me if we allocate to cures.
I'm genuinely glad you have new treatments and its improving your quality of life.
The point I am making is that you are a/ not getting cured, and b/ paying a lot of money. The reason for this, is this is best strategy for maximising profits. Its really the exact same model as your local heroin/crack dealer.
Please set me straight if those conditions differ in your case.
Profits are what pharma companies want.
The consumer is mostly labouring under the illusion that companies want the best for you. They are not your mum. They want what's best for them. And, most people would do the same - no one is gifting anyone health.
All I'm saying is let's drop the illusions and fantasy and call a spade a spade.
The local illicit drug dealer comparison doesn't apply because you can't simply ignore the development time and cost of FDA approved drugs. My post was about allocating limited capital to pharmaceutical research, and maximizing benefit.
Again, if your choice is improving quality of care for 100 conditions or trying to moonshot your way to curing one disease, more patients benefit from the former even if pharma also profits more.
> Which illnesses have been cured? Diabetes, cancer?
Type I diabetes - no, but this is a condition in which the body attacks the part of itself that makes insulin. So by the time it happens, it's too late. Sadly, we're generally bad at understanding and preventing autoimmune diseases, but this needs more basic research, not drugs.
Type II diabetes - essentially a lifestyle condition. May be functionally cured in some/many cases with strict lifestyle interventions. Ironically, GLP-1s may help move some people towards a functional cure.
Cancer - yes, where possible. The open secret is that the best way to fight cancer is to not get it in the first place, or failing that to catch it very early, but these are issues of lifestyle and public health policy - both of which we're currently very bad at optimising, as a species.
> All the financial upside for pharmaceuticals is in prolonged treatments.
Even without understanding pharmaceutical research, your claim to understanding business strategy is braindead: there is not 1 pharmaceutical company. And many pharmaceutical companies work on treatments for the same conditions and diseases.
Why would any competitor sit on a cure for a condition there opponents can only treat when in the short term you'd post amazing next quarter profits, and in the long term you'd financially diminish that competitor in the market place even if we grant the position that you are somehow able to find treatments that aren't cures (others have explained ably why this isn't how it works).
Everything looks like a conspiracy when you don't understand anything.
They want something that actually works, foremost. If the thing they sell doesn't work, then when someone figures out something that does work the thing that works will be preferred by the doctors.
to put a finer point on it, to be able to gouge sick and slowly-going-crazy people for lots of money you have to have something that actually solves the problem.
can't mark-up snake oil, not in ways to shift the stock price for Fortune 100 tier companies -- too many lawsuits and visibility
"Despite being described as a “cabal,” the amyloid camp was neither organized nor nefarious. Those who championed the amyloid hypothesis truly believed it, and thought that focusing money and attention on it rather than competing ideas was the surest way to an effective drug.
It has not worked out that way. Research focused on amyloid, and the development and testing of experimental drugs targeting it, have sucked up billions of dollars in government, foundation, and pharma funding with nothing to show for it. While targeting amyloid may or may not be necessary to treat Alzheimer’s, it is not sufficient, and the additional steps almost certainly include those that were ignored, even censored. Probably the most shattering turn came in March, when Biogen halted the study of what proponents called the most promising Alzheimer’s drug in years — an amyloid-targeting antibody."
I still refer to this article seven years later. Groupthink in the medical research space sets back progress by decades. And it's not just Alzheimers. The FDA's approval process is stymied by a CYA culture that fails to adopt the risk profile it needs to in order to potentially save large contingents of sick and dying.
> The FDA's approval process is stymied by a CYA culture that fails to adopt the risk profile it needs to in order to potentially save large contingents of sick and dying.
Except the history of FDA approval here is that it has been too accepting of drug candidates for Alzheimers with very weak evidence of efficacy and serious side effects. This particular field would probably be better off if the FDA took a harder position on efficacy, rather than deferring to drug companies and patient/caregiver groups that desperately want something.
I would like to see the FDA get rid of their binary "Approved" approach.
Instead, at the start of a treatment on a patient, an analysis must be done of all available data, and the treatment only allowed if the error bars put it within the realm of the best treatment available.
That means at the start when not much data is available, it is easy to give it to a patient. But over time as more data comes in it gets harder and harder to do so if the treatment is ineffective or harmful.
Data should be collected and analyzed in real-time - it should be a matter of hours between some life event like a death feeding into the dataset used for decisions on new patients.
The struggle is the high level regulatory bodies (with the exception of aberrations such as the current admin's approach to appointment) generally select for individuals with a low risk tolerance. Low risk tolerance is generally incompatible with speed - it's a miracle the covid vax and treatments were approved as quickly as they were in 2020.
Biggest example of this risk aversion is the peptide craze going on (the most famous of which are GLP-1 antagonists). It's pretty much a wild west where people read a low-sample animal study, and buy a drug that's "for research only, not for human consumption" off of a compounding pharmacy in China.
Few human studies because even if you have willing and enthusiastic volunteers it's too expensive and creates legal liability. And the FDA cannot approve it without a high bar of evidence (for effective treatment and low risk) and costly, time consuming reviews. Because of this, there is a black market for the things and people are basically being their own test subjects.
> The struggle is the high level regulatory bodies (with the exception of aberrations such as the current admin's approach to appointment) generally select for individuals with a low risk tolerance.
This may be true, but I don't think it's the major driver of conservatism. Two thoughts/observations:
1) Bodies like the FDA face a strongly skewed set of incentives. If they take a risk on something and people get hurt, they face huge public criticism. If they take a risk on something and it's all fine, very few people care or notice. As such, they are strongly driven to not make a public mistake - which drives ever more conservatism.
2) FDA can actually be innovative compared to other health authorities. Breakthrough therapy designation, Project Optimus, Project Frontrunner, and others - show this. However, they've got a strong 'not invented here' mindset - they flatly refuse well-meaning individual innovations from pharma companies, if they're not compatible with FDA's guidelines. And they're heavily bureaucratic, meaning the innovations that do appear are usually following years of process (which probably links back to #1).
This does happen. SAEs are reported in real time, and they do halt trials sometimes. Also, there is often a condition of approval that requires ongoing data collection for adverse events post-approval.
I was outraged when I first read that article, but taking a step back and catching up on recent progress, I came to the same conclusion you did. Words like "nefarious", "fraud", and "corrupt" were thrown around, but no one was actively was seeking to do harm.
The harm was done by the groupthink and the sucking up of resources to research alternative causes. One of the comments on HN when that statnews article was first linked was by a commenter who worked on Alzheimer's. They agreed and I remember the line, (something to the effect of) "if you wanted funding for alternative investigations, you had to still throw a bone to beta amyloid in your proposal."
Was it all a waste? No. Current thought is beta amyloid is still involved, but Alzheimer's is multicausal. What those other causes are is in its investigation infancy. We could have started investigating those decades ago if the scientific research complex were truly open to new ideas.
This is similar to what we see in software architecture. There's a team that picks a framework or pattern early, then builds everything on top of it, and by the time evidence shows up that the foundation was wrong. Now, switching costs are so high that it's cheaper to keep building on the broken foundation than to start over. The amyloid hypothesis reminds me of technical debt. The "cabal" wasn't conspiring, but they were just rationally protecting their sunk costs, same as any engineering org that can't migrate off a bad database choice.
There's a lot of this going on in science. Once the common accepted truth is "X" papers that are counter to X or show that X is not true, end up not getting published and then funding dries up.
They say science advance one death at a time.. let's hope LLM/AI can fix that by giving resource previously inaccessible to smaller players to be able to show results against the consensus.
Otherwise we just need to hope that we live long enough and don't catch ALZ until the current ruling peer group pass.
The major problem has been lock-in of the Abeta 42 peptide fragment as the cause. This monomaniacal focus was rewarded by grant awards to team players.
Karl Herrup has a terrific book on the topic How Not to Study a Disease — The Story of Alzheimer’s from MIT Press (2021, ISBN 9780262045902). He did not win many friends but I think he is right.
The consensus now is that many factors contribute to the heterogeneous diseases we now call Alzheimer’s.
The article (or I guess more accurately "podcast transcription") seems to be saying that this lock-in essentially happened due to fraud, since some of the data was intentionally doctored to get the intended result. One of the guests seems to be an author of a different book about this (with the other guest being the scientist who apparently uncovered this). I can't personally attest to the accuracy of anything they said, but they're at least alleging that it was a lot less benign than it sounds like you're describing.
The focus is definitely on scientific fraud, but what makes the fraud so easy in this case is singing and selling the same song that the big teams are singing and selling. You can fly under the radar AND get funded, and if you are “lucky” become an ultra big shot like Masliah at NIA.
I don't buy the fraud explanation as the full explanation. Other areas of medicine (stem cell) has had bigger incidents of fraud on top of other major headwinds, and still has made more progress.
Fraud is everywhere and we still move forward in most arenas.
In ALZ and the plaque cartel the fraud was foundational and the overwhelming source of funding for research was tied to supporting that hypothesis. The big issue, even if you have a competing theory, is that the diagnostic criteria relies heavily on the plaque and presence of indicators. So you get a group of people who have elevated plaque and MCI, but many people have elevated plaque without MCI, and just as many people have MCI without elevated plaque.
So if your cure is targeting something different but the group of people you have are selected from this cohort of maybe afflicted people then it's really hard to get a significant result. Plus you tend to be dealing with old people, that have other health issues that MCI isn't causing to get any better.
The stem cell field is also quirky. IMO it is one of the most cutthroat, competitive, ruthless fields of life sciences that is new enough in history to still have a bunch of pioneers fighting to be the figurative Oppenheimer. One PI’s fraud is quickly detected and fought over.
Meanwhile the Alz and Neuro field as a whole are well established, and the amyloid hypothesis was a foundational theory taken as a fact. Any initial questioning of this and they would brand you as a lunatic.
There’s another book mentioned in the podcast called “Doctored.” The gist is: bogus “science” led to loads of money / research going in a direction that was effectively fiction.
People love to praise “the science” when they mean the scientific method. What they always seem to forget is that method is executed by humans. Imperfect, sometimes ego driven humans.
The genetic evidence that amyloid-beta is in some way causative of at least a subset of Alzheimer's disease is still extremely strong.
The fact that amyloid-beta binding drugs like Lecanemab and Donanemab decrease progression is also very strong evidence for the amyloid-beta hypothesis.
What seemed to be the hurdle was likely, that targeting amyloid-beta in its pathological form just wasn't easy and developers of pharmaceuticals instead focused (for unknown reasons) on the solid amyloid-beta grains in the brain.
The major reason things are moving so slowly is because of the long development times of pharmaceutical compounds. A new compound will at least have to spend 2-3 years in safety studies before being tested on its first real patient, and then for Alzheimer's, which is a slowly developing disorder, nothing short of a 2-year followup time will show efficacy unless it's truly a miracle compound.
Unfortunately the evidence that targeting amyloid (e.g. Lecanemab and Donanemab) improves the symptoms of Alzheimer's disease is very weak. See the latest systematic review [0]. This does not mean however that amyloid plays no role in the disease, the treatment may simply be too late.
That systematic review is unfortunately severely flawed. They pooled the old anti-amyloid antibodies (which everybody agrees are inefficacious) and were never used outside clinical trials, with the new anti-amyloid antibodies, that does show modest efficacy in reducing the speed of progression.
While these two classes of drugs target the same molecule, they are developed to target amyloid-beta in very different forms. Pooling all those drugs together, and then showing very weak effect, makes absolutely zero sense, and I hope and expect this review to be pulled soon.
The point of systematic reviews is to be un-biased. So if their question is whether targeting Aβ amyloid is a valid approach they have to include the unsuccessful trails as well as those purported to be successful.
As to the trials specifically for Lecanemab and Donanemab, the benefits are not claimed to be either strong or large, even by those who support it. The current support these receive is more aligned with the concept that an improved targeting of Aβ amyloid might improve outcomes. This remains to be demonstrated.
I don’t quite follow the reasoning behind this being “unbiased”. Studies must be designed to answer specific research question. What is the question being asked by the study in question. If the question being asked is whether AB the right target (in humans), then it would need to consider other forms of human evidence, such as genetic evidence, alongside alternative explanations of failure — bad molecule, wrong isoform, bad cohort selection, etc.
The question asked in the Cochrane review linked to above is whether there is evidence that current treatments targeting amyloid provide relief. Their conclusion is that the effect is too small to be considered beneficial.
Especially when considering the undoubted side-effects, which include edema and micro-bleeding in the brain.
It doesn't ask whether amyloid is causative of the disease.
I wonder. Because if that was the question, why would they include anti-amyloid treatments that were never approved and are not part of any current treatment regimen and dilute the real effect of the approved antibodies? (Not that the approved antibodies are a silver bullet, but clearly they have some positive effect.)
The Cochrane review did not ask the question of whether Lecanemab (for example) worked, it asked the more general question of whether targeting amyloid worked. If targeting amyloid, generally, worked you might expect all approaches to targeting amyloid to show some efficacy. So they included all those for which clinical trials had been conducted. Obviously some treatments didn't pass the threshold required and so were not subsequently approved. If you only included successful trials you would bias the outcome.
It's possible, of course, that some methods of targeting amyloid might work where others failed. But even those that claim success (Donanemab and Lecanemab) have a very modest benefit.
Yes, the new anti-amyloids are not a revolutionary therapy. But they do have a small but definite effect on disease-progression. (something which in a highly noisy indication like Alzheimer's may actually mean a lot more to the patients than it seems by looking at the data. E.g. donepezil and memantine have very modest effects too, but patients and caregivers are still surprisingly positive about them).
And since these were developed using different methods and epitopes, it does not make sense to pool them together when doing a comparison. It's obvious that if you combine modestly beneficial compounds and compounds with zero beneficial effect then the mean effect will be worse than the modestly beneficial compounds.
And when you do so just because they were aimed at the same molecular target, not even considering if anyone claims that the old, unapproved antibody-therapies, with no positive studies to support them, have any effect, what you are doing is somewhere between extreme ignorance and deception.
All the trials included in the Cochrane review demonstrated removal of Aβ amyloid from the brain. Side effects were relatively modest, except for edema and micro-bleeds. So they are all legitimate tests of the hypothesis that removing Aβ amyloid would be beneficial.
No you would not expect all efforts to target AB to work. You can have the right target and the wrong molecule. Look at GLP1s as an example. Multiple pharma companies tried GLP1 receptor agonists for more than a decade and it was not until recently that Novo and Lilly got them to work.
But has only weak/moderate effect on weight loss compared to semaglutide, tirzepatide and retatrutide.
Alzheimer is a lot more difficult to measure than weight and amyloid-beta in the brain obviously significantly harder to target than the GLP-1 receptor in the body.
Also, a review pooling together all GLP-1's (including those that failed in development) and concluding that they as a class have only moderate or weak effect on weight loss, would obviously be badly misleading.
If you grouped all GLP-1 agonists that had entered clinical trials, they would be shown as successful [0]. No GLP-1 receptor agonist has failed to reduce appetite in clinical trials, but some were better than others.
The point about the anti-amyloid trials is that they all succeeded in removing amyloid. But they did not improve cognition, and only some resulted in a slightly slower rate of decline in cognition (people still declined).
>Forty-seven RCTs were included, with a combined cohort of 23,244 patients. GLP-1 RAs demonstrated a mean weight reduction of -4.57 kg (95% CI -5.35 to -3.78), mean BMI reduction of -2.07 kg/m2 (95% CI -2.53 to -1.62), and mean waist circumference reduction of -4.55 cm (95% CI -5.72 to -3.38) compared with placebo.
Your meta review has like 80%-90% of the studies on semaglutide and liraglutide. When finding random effect per drug, they even say this:
> Hence, the drugs eligible for meta-regression were semaglutide (subcutaneous injection, once weekly) and liraglutide (subcutaneous injection, once daily), which both showed a dose-dependent treatment effect in terms of weight and BMI.
And the class-effect is much more modest than semaglutide by itself would have shown, exactly as I said. What is the point?
Both meta-analyses above cover all eligible clinical trials for the respective strategies, targeting the GLP-1 receptor, or targeting amyloid.
For the GLP-1 strategy, Table 1 in the above paper shows that all drugs were clearly effective. Some were better than others.
For the amyloid strategy, only some of the drugs were effective, and that efficacy was very weak, even when all the drugs removed amyloid. This brings into question the hypothesis that removing amyloid would alleviate AD, i.e. the slender benefits of Lecanemab might not be caused by amyloid removal. The same cannot be said for the GLP-1 receptor agonists.
Agreed, especially in some subpopulations. I think the strong case today is to research it's use in people with Dawn's syndrome (accelerated development Alzheimer's Disease due to 3 copies of the APP gene). Target it only to people with those 3 copies.
It's legimate as people with DS have a hugely increased risk of AD.
Their risk increase seems likely related specifically to Amyloid.
Many with DS can consent to it.
In general my completely gut feeling is that once we can target Tau we might find that targeting amyloid is needed to fully curtail progression.
Agreed, using these anti-amyloid treatments at an early stage in people with a high risk of early onset Alzheimer's disease, such as those with Down's syndrome, is likely the most robust test available of the theory that Aβ amyloid is directly causative of this disease.
Trials are currently ongoing. The results should start trickling out in a few years...
I'm surprised there was no mention (at least none that I found when searching) of the relatively recent research coming out of Harvard regarding the hypothesis that low levels of lithium in the brain are responsible for a lot of Alzheimer's cases.
The research is still in the very early stages (largely mouse models, though they did develop the hypothesis by looking at differences in human brain tissue post mortem), but to me my biggest fear is that little research will be done because the "cure" is a commonly available, non-patentable supplement, lithium orotate.
As someone in middle age with a family history of dementia, I've decided to start taking lithium orotate because the risk/reward profile looks so good from my perspective. Lithium orotate has been sold as a supplement for decades, and at those levels it is very safe with extremely-small-to-no chance of adverse effects (e.g. https://www.sciencedirect.com/science/article/pii/S027323002...), so I figure the worst that can happen is I'm wasting my money, but I'd take that for even the small chance that it helps ward off dementia.
Interesting. I'm also taking orotate, and like the other comment here, it makes me very sleepy (so I'm taking much less than 1mg/day). Maybe that's the brain working to "take out the trash?"
Earlier today I read a comment here mentioning Dr Michael Nehls who writes about lithium and also dementia (highly recommend his books). Now that comment is no longer there. Hmmm.
I agree with your post and the well-studied safety of it in humans at appropriate doses :) but the study you linked is on rats; and so there’s probably another better study to link.
I experiment and take a small number of less-commonly-known supplements and those kind of studies _in itself_ should never contribute to “it’s safe for humans”.
Anecdata: my personal brain/body didn’t react too well to 1mg a day, I felt somewhat ‘sluggish’ and found concentrating harder, so I stopped after 2 days out of being conservative. Perhaps I’d get used to it, but for me personally, I was surprised at the effects of just 1mg so I didn’t want to continue taking it.
To add some context on the study I linked - that particular study was only focused on understanding why, after decades of use by humans as a supplement, that lithium orotate has so rarely been reported in any cases of adverse effects (all the cases I could find were acute toxicity from taking way too much, like the 18 year old woman who took 18 capsules at once, and still only suffered nausea and some mild tremors). So that study found none of the effects on specific organ systems in rats that you often find in other substances that have higher rates of adverse effects.
My point being, if that was the only safety study done on a brand new substance, I'd agree with you, but the safety profile really boils down to the decades of human use as a supplement.
All that said, I totally agree that many more human studies are needed to determine the actual efficacy of lithium orotate in preventing or reversing dementia.
It’s actually quite simple: 1–5 mg lithium orotate, vitamin D, omega-3 from algae with high levels of polyphenols, a daily exercise routine, and good food—not the processed crap you often get in the US. My grandmother is 94 and still mentally so sharp that she amazes me every time.
It's actually not "quite simple" at all, and I think there is a gulf of difference (often misunderstood) about taking supplements as a personal decision because there is low risk of harm, there is some preliminary evidence they may be helpful, and one can afford them, versus touting them with certainty as the cure to a whole host of ailments without sufficient evidence, which is usually what "wellness influencers" and people selling supplements and "health optimization" programs do.
My grandmother lived to 102 and was mentally sharp right up until she died. She also smoked daily into her 90s.
Any side effect goes away if you reduce the dosage sufficiently. In the recent Harvard study the dose was very small when you convert it to a human equivalent dose.
I took lithium for <redacted tendancy> it got to my kidneys never thought of more generally microdosing lithium. Interesting. Full dose yeah flat and sleepy. Not sure it was the reason for flat out brain rot. (Other factors were available maybe just getting older.) Full dose needs blood tests as overdose weirdly bad. From <relative> due to dehydration / holiday in the sun looked like almost drunk but not drinking slopy etc. Slightly clingy desparate for interaction with strangers. <Other factors could have been available>. Not informed of damage relative seemed to recover ok. <Nationalised medical system>.
"Do not attribute to malice what can be attributed to incompetence" and all of that, but...
Alzheimer's (like a gazillion other diseases) is a product of senescence, and senescence is a subject that faces strong ideological headwinds. That leaves the medical system in a situation where they want to treat the symptoms (the diseases) instead of the root cause, and treating the set of symptoms that we call Alzheimer's is going to be tough.
The single best predictor of Alzheimer’s disease is chronological age. Yet of NIA’s $4.5B FY2025 budget, about 60% goes to Alzheimer’s and related dementias; only 9% to the Division of Aging Biology, which funds the basic mechanisms of aging itself.
The insider joke is that the “A” in NIA stands for Alzheimer’s. The deeper and sadder joke: when you fit cognitive trajectories within the subset of people who go on to develop AD, about half of the variance in their test scores is accounted for by chronological age alone.
We’re spending seven times more on the disease than on the clock — and the disease is mostly the aging clock.
As a society we are so used to seeing our grandparents and parents die that thinking otherwise is near impossible. I wish we saw ageing as a disease it is, instead of a "natural therefore good" thing.
Yes, and less than $1 billion/year spent on the basic biology of aging by NIH/NIA. Funding for research on the root causes of aging is decimal dust compared to distal consequences such as cancers, cardiopulmonary diseases, renal failure, immune diseases, Alzheimer’s, etc.
NIH is great at tactical research but terrible at strategic research, and politicians do not help much ;-)
The brain is a dynamic system, and a poorly understood one at that. It relies on active processes in order to not degenerate (likely the main reason why sleep deprivation is eventually fatal). Science is still some way from cataloguing all the processes involved, never mind fully understanding their workings.
Alzheimer's isn't a single-point-of-failure disease, more like a dysregulation of maintenance. So there are lots of things that can tip the odds one way or another, and we may get a lot better at prevention - to the point of reducing incidence maybe five-fold, or delaying its symptomatic onset to beyond the relevant lifespan - but the idea that there might be a single "cure" seems like wishful thinking.
It may also prove to be that, like a spinning-top, once things start to go off-axis it may be very difficult to restore the original stable state, and at most we can just slow it down a bit.
Perhaps more uncomfortable, if most of the effective interventions, risk-reduction-wise, are social/lifestyle related, that has implications for whether people have the agency to access those things.
(Time/energy/facilities/resources for exercise/active lifestyle being an obvious case in point, which is already well known to have a moderate protective effect).
Unable to read the full article, however the amyloid hypothesis is not without solid scientific foundations.
Alzheimer's disease may occur either due to inherited mutations in the genes for APP or presenilin, in which case it can occur as young as 40 yrs old. Or it may occur "sporadically" in those over 65yrs old. The brain pathology of both is similar. Notably, amyloid is derived from APP in part by the action of presenilin, which cuts the APP protein to release the amyloid peptide (Aβ).
Currently, the amyloid hypothesis is the only known way to reconcile the similarity of pathology (for both amyloid and tau) between early onset inherited AD caused by mutations in either APP or presenilin, and later onset sporadic disease. Furthermore, all the mutations in APP that cause Alzheimer's disease are located within or adjacent to the region that corresponds to Aβ amyloid, and not in the remaining 95% of the molecule.
Until another way of unifying these observations is found, the amyloid hypothesis will always find supporters.
I did undergrad research on amyloid aggregates in 2010, with Alzheimer's as the motivation. I remember papers coming out then making it pretty clear that there was no real mechanistic link between them. It was basically just a symptom. That was 16 years ago.
'Science progresses one funeral at a time...' It is often the case that an entire field is led by a few influential people and until they leave others can't get the air they need to make real progress.
I'd argue the reason we’ve spun our wheels on Alzheimer's for decades isn't just about a flawed amyloid model. It’s a symptom of a much larger, dying paradigm in biotech.
For decades, the industry standard was to hunt for targeted small molecules to solve singular biological issues. And to be fair, I don't think this was because of a lack of vision as it was simply the strict limit of our technological capabilities at the time. But attempting to treat a cascading, systemic disease like Alzheimer's with a single targeted molecule is like hoping replacing one pipe will solve the problem when the issue is that the entire plumbing system is corroding.
This fundamental mismatch is exactly why clinical progress has stalled, and I believe the future of treating Alzheimer's will instead closely mirror how our approach to oncology has evolved.
We spent years searching for a universal molecule to cure cancer before we accepted reality. We now know that effective treatment often requires sequencing a tumor's mutanome to develop a highly personalized intervention for the individual. As neurodegenerative systems fail with age, we face that exact same biological complexity. A traditional small molecule is not going to rescue a globally failing network.
My personal take is that we won't see a true breakthrough in Alzheimer's until capital fully rotates out of these legacy, single-target pipelines and into programmable biological systems.
> gatekeepers directly or indirectly control research funding.
Perhaps funding like public grants could be controlled by few? Should not the case for private money?
Relatively common health issues older people tend to get fair amount of private funding after all.
Rich people tend to be older and they are lot more likely to see amongst their friends and family Alzheimer's and Parkison's or even cancer and so forth and be worried about it and thus donate money to them.
In somewhat related (i.e. old people health concerns) life extension research gets all kinds of wacky non traditional research lines get funded all the time, I don't understand why would Alzheimer's would be any different.
If you're a wealthy person lacking a neurobiology background, how do you decide which research efforts are the most promising? Which labs do you back?
Generally, you rely on experts.
Who typically became experts by adhering to the conventional wisdom set by gatekeepers.
"Science advances one funeral at a time" feels apt.
Sadly, the problem isn't confined to Alzheimer's.
Whenever only a few people decide what is "right," the same pattern of stifled innovation will generally manifest itself not by design or from malice, but because it's hard for a small group to be 100% right on what works and what doesn't -- especially on matters as inscrutable as neuroimmune diseases.
I don't think the problem is nearly as big as people claim. Experts are often right!
While there are counter examples and inefficiencies in the system (and there are idea of addressing this, by distributing some part of the money in other ways), we have far bigger societal issues because people do not believe in science, especially where there is an industry lobby sowing doubts.
So I really want to push back against the the idea that the scientific system is broken. While there are real issues, this is still very misleading.
What also happens is these gatekeepers end up being those requested to review papers. When a paper comes up for review that challenges the status quo these gatekeepers nit-pick the paper and recommend it not be published. This happened to my wife on numerous occasions. She has a few unpublished papers because of this. What she found in her research has since become the common accepted knowledge in her field after a few funerals.
Life extension seems like the kind of thing that can get private funding with relative ease specifically because they aren't trying to compete with the government. There are a lot of private foundations that give out grants too though.
Life extension in the private sector is dominated by hocus-pocus and unwarranted optimism. The genetics of mortality is amazingly complex. See this open access monster paper that came out in Nature this week—admittedly “in mice” on mortality and genetic of longevity.
In most engineering fields we don't give the monopoly to people until they have actually demonstrated success beyond a reasonable doubt. There will always be groups of people claiming that the math/methods they happen to know are the best at explaining some behavior (even now there is that learning mechanics paper on top page)
The takeaway is to stop pretending that we can do good science when the ambiguity is so high, the majority of funding should go to people working on more concrete problems. We never locked in on vacuum tubes because the downsides were so obvious and the upsides of silicon transistors (if they could be made to work) were also obvious even to people outside the field, where your talent comes from. At the very least funders can't allow shifting goalposts, make them up front answer questions about the drugs. That will give you something to estimate the value of the drug and then when they come back with study after study outside the ranges they gave, you lower their funding. E.g. This is supposed to work on someone who was stage 2 and stop progression and then 5 years later it only "works" for stage 1 patients.
Strange breakthrough ideas can't even exist in the current system structurally, so going this route is the only logical choice. Which begs the question, why aren't clinical trials a private venture already? Governments are burning billions of taxpayer dollars for either nothing or cynically to keep the boomers alive and voting even longer, while 1/5 children are obese. For the rest of us we've socialized the risk and privatized the profits.
It's because there is little progress in uncovering the mechanisms of the disease. Alzheimer's et al are tau-opathies and Parkinson's et al are synuclein-opathies. Both are degenerative and we wait for their common base in a Grand Unified Theory.
I like to view degeneration of any tissue as death due to (premature) aging. So, if we treat it, we achieve immortality by applying it to all body. This is something hard.
There has been massive progress in neurodegeneration research. We now understand that the brain has a complex system for processing metabolic "trash." Like all systems it has a number of components, each of which can fail. This is why a single "silver bullet" drug will likely never exist. A multi variable systems failure can not be fixed with a single variable solution.
Alzheimer’s occurs when Amyloid/Tau debris accumulates faster than the glymphatic system can export it.
Parkinson’s occurs when α-synuclein (Lewy Bodies) accumulates because the cellular recycling system (Mitophagy) has failed.
While Choline is a critical bottleneck for Alzheimer's, Glutathione and GBA enzyme activity are the primary bottlenecks for Parkinson’s. But in both cases it depends on the person and their genetics and what matters the most. If someone is at high risk for Alzheimer's a multi-pronged approach will probably be very common. For example a post menopause woman who is not on HRT, but at high risk due to parents should be getting Choline due to the low PEMT expression, but they might have a higher risk for neuroinflammation via NLRP3 and so need to also combat that too.
To say no progress has been made is to ignore the fact that we have learned a ton about the various components of these systems and how they can break down.
Here are the two approximate decay equations that you can put into an online latex viewer.
The point of these isn't to give an exact equation, but to make the understanding of the systems and their components radically simpler for humans to understand which can help with treatment leading to questions like "Where is the bottleneck in this patients system?”
Elaborating a bit - brain is hard to study since you can't easily take a biopsy of it (from a living person at least), and various brain scans are not great at identifying the stuff we care about.
The slow acting nature of it means also you have to wait a long time to see results of clinical trials; also because early stages are easy to miss that also means you are stuck studying people who are already pretty senile and thus might be beyond the point where you can make a big difference.
Ruxandra has a nice piece, focused on cancer, but the reasoning is basically the same here: biology is just really hard. Sometimes we get lucky but in general it's a long, slow slog.
And as with a lot of cancers, it seems to be perturbation of a dynamic system rather than a single, mechanistic cause.
Think of it like brushfire in an ecosystem, or species population imbalances leading to catastrophic breakdown. These are better understood in terms of system state and preconditions, as opposed to a trigger event.
Infectious disease, at least in the classic acute form (whether that's bacterial and fast - cholera - or viral and slow - HIV), is a more mechanistic process which can be halted by blocking a single step in its pathway.
Systems that remain healthy and balanced via dynamic processes are harder to reason about and fix, because the root cause of a disease state can be dozens of little things adding up to the system losing its ability to maintain homeostasis.
Just like that math problem, we are starting off with wrong thinking right from the beginning. Some researchers are already talking about this but the plaques are actually a protective response to a metabolic problem in the brain which has to do with glucose transport.
One of the most important ingredients of a proposal for a drug development program is viability: is there a path to market. The issue with Alzheimer’s is that until recently there was no practical diagnostic test. Without a test, there is no way to run a clinical trial. No clinical trial means no drug approval. Research is halted before it even begins.
No it isn't. There's little evidence this drug works beyond some small studies done in Cuba by the people who developed the drug. The sum total of medical tourism to Cuba is quite small, no more than about 10k people per year. This is large due to their healthcare system lacking basic supplies like gauze and aspirin. Belly of the Beast isn't a real news outlet, its propaganda.
What is "a lot" of tourism is arbitrary but Cuba is obviously one of the most commonly talked about medical tourist destinations. Despite being strangled by the longest running US embargo (66 years) they managed to make a remarkable and free healthcare system. According to the World Bank and WHO they have the most doctors per capita of any country. Anyone that's worked in international crises is well aware of Cuba's army of doctors that they send to help out in disasters
> but Cuba is obviously one of the most commonly talked about medical tourist destinations.
No it isn't, and not by a long shot. The vast majority of medical tourists to Cuba are from the Caribbean, virtually no one else goes there for medical care. If you have money to travel for healthcare there are tons of better options, and most countries with national systems have VASTY superior facilities.
> Despite being strangled by the longest running US embargo
The US embargo which I don't support doesn't cover medical or agricultural goods. The Cubans received free oil and equipment from the USSR then Venezuela, and still couldn't manage to maintain any infrastructure. They can trade with any companies that aren't US based, and do. Their largest trade partners are Spain, and for agricultural goods the US. However the country is so badly managed and corrupt that they've turned all of that free oil, industrial equipment, and expertise into abject failure.
> remarkable and free healthcare system.
It's actually dog shit, and their own government admits that its plagued by shortages[1][2]. I personally have known several people who go there to perform free eye surgeries and have to bring their own equipment because the Cuban system doesn't have any.
> Anyone that's worked in international crises is well aware of Cuba's army of doctor
The UN has called this slave labor[3] on several occasions, and many people I've talked to who have worked with MSF and otehr international medical aid orgs all say the Cuban doctors are so poorly trained as to be dangerous to patients. The lack of materials in Cuba means they never get hands on experience with vital techniques.
Surprised to see anyone mentioning this here, NeuralCIM has been talked about for years behind the iron curtain. They also developed their own COVID vaccine and send hundreds of thousands of doctors to countries in the global south but even rich nations when they need help dealing with natural disasters. The US is viciously targeting them doing incredible harm nobody ever talks about.
It's good to expose fraud and it does sound like this set back the field, but "Why has there been so little progress"? - probably because it's very hard? We barely understand how the brain stores memories.
I'm dealing with someone with this disease now and it's absolutely hell.
Because of Joy, scientists developed a simple, non-invasive, three-minute skin swab test that analyzes sebum to diagnose Parkinson's. In laboratory settings, this test has shown an accuracy rate of over 90%.
Unfortunately that insight hasn't led closer to a cure.
It also turns out sort of bad to tell people they have a horrible neurodegenerative disease 10 years before the major symptoms start.
Why isn't everyone's mind blown? Well for the cynical explanation, look at the state of science education and what people said about Artemis, vaccines, etc. or optimistically, there are too many mind blowing discoveries to treat them all fairly.
This is what the replication crisis looks like in tangible effect. I feel that consensus around major questions should never form without totally independent confirmation of experimental results. Even if not due to intentional fraud, you have to worry about, systematic errors, p-hacking, or sheer statistics (a million experiments performed by researchers is likely to yield at least one 1-in-a-million statistical fluctuation that looks like a genuine result).
I'm not saying I'm the best informed on this topic, but I thought the root cause has been known for a long time now as degraded endocrine and cardiovascular function.
That's also why Alzheimer's can take so long to develop. It's just one aspect that we've chosen to focus on because it's more clearly noticeable, but it cannot easily be treated in isolation from everything else. If it was, it would regress quickly without fixing the root causes.
We truly do not know the root cause. There are plenty of folks with "degraded" endocrine, cardiovascular, and both systems. Most of them do not develop Alzheimer's.
There is no single root cause. Many scientists have preferred to ignore this fact and that has been a serious problem. Everyone likes a simple story. Age-related diseases are not simple stories.
No mention of Leqembi or Kinsula? Both FDA approved. And Simufilam that was mentioned was cancelled because of a failed phase III study years ago.
But fair, improved biomarker data does not mean the drug is making any real improvements for the patients especially with the side effects. But it is also well known.
It's not just that one paper may have been wrong; it's that a fragile consensus can redirect billions of dollars and decades of work. Alzheimer's is also a brutally complex disease, so the opportunity cost of narrowing the search too early may have been enormous
Because of almost certainly fraudulent science. See https://www.science.org/content/article/potential-fabricatio.... Research was misled for decades down the path of assuming that Amyloid plaques are causative of Alzheimers, a now disproven theory (there's an association, but that's not the same as causative.)
Scientist Ruth Itzhaki spent years studying a far more promising theory of Alzheimer's: that it's caused by viral infection in the brain, particularly HSV-1, best known for causing cold sores. Most have it, so there are clearly other factors at work, likely related to susceptibility in particular individuals to to the virus infecting the brain and spreading over time. See https://pubmed.ncbi.nlm.nih.gov/34205498/
The implication is that anti-viral treatments are likely to inhibit and potentially cure Alzheimer's. There is already unintended evidence along these lines, both via antiviral drugs and vaccines.
I see several people here who appear to be replying to the headline rather than actually reading the article (well, podcast transcript, technically). What you mention is already discussed extensively in the podcast episode, and Matt Shrag (the scientist your first link is about) is the one being interviewed in the podcast.
The most complicated known object in the universe, and a disease that attacks the one thing that sets it apart from everything else. No surprise progress is slow in coming.
Given the fertility crisis, you would think that linking a devastating disease to a common and incurable STI would make the both of them top priorities.
Type-3 diabetes? It's degraded endocrine and cardiovascular functionality. Basically, your enzymes stop producing -- things like testosterone and insulin. Your lungs stop working as efficiently, and your brain just gives out.
If you're looking to beat type-3 diabetes, you need to have a daily routine of exercise while you're young to keep these systems in shape when you're old.
You also don't need to belong to any marginalized groups, as ACEs tend to wear your body out over time -- breathing, kidneys, and heart in particular. People with traumatic childhoods (bullying, abusive parents, etc) have a huge risk of dying of dementia -- if their kidneys don't give out first.
Alzheimer’s is a good example of a disease where we don’t have great scientific understanding on the underlying causes, but that doesn’t stop individuals from believing they understand it better than the scientists.
Actual Scientists are calling it Type-3. But these are the same scientists that are actually reversing Type 2 diabetes without expensive drugs. Of course they exist outside the pharma narrative, and they don't have any uncurious attack dogs willing to defend their narrative-busting results.
Are recurrent childhood neglect and abuse events not an antecedent to mental health morbidity in adulthood, which then creates missed opportunities for growth and necessitates and the need for the use of medications?
I think you’re making a giant leap from A to Z and missing a whole bunch in between.
All I know is that people with higher ACE scores have higher dementia rates. And that higher ACE scores are linked with heart failure, lung failure, and kidney failure.
Stress ages the body. Homeless people can age several years, being on the streets for just a few months.
I've also seen numerous people in these upbringings die in their 50s and 60s from kidney failure. My stepdad was one of them. My father too.
My father had a normal childhood, except he had a traumatic experience of shooting his twin brother while they were playing cowboys and indians. Spent his entire life blaming himself. Went through all the normal development phases. Not on any meds.
His body just started shutting down prematurely. It's common in people with those experiences. First, his breathing got bad. Then his kidneys. Then he started having heart problems.
And that's the pattern. Heart, lungs, kidneys. Which are all linked to the brain. And eventually lead to dementia-like symptoms. At least that's what the research on ACEs seems to point out.
I'll say that I know nothing about this, but just commenting on the economics of it all: Cancer and HIV have been at the forefront of disease research, in terms of public interest and financial investment, and cancer is more like an umbrella of similar diseases than a single disorder. HIV is manageable these days, and cancer research is slowly seeing leaps in progress.
Alzheimer is very important, and affects a very large number of people, it is getting lots of research funding and attention, but perhaps not enough? If it takes a certain combination of time, human-hours, money, and lots of smart people being interested in doing research in that field. Is the economics of disease research that simple? it is unknown what numeration of those variables is required to tackle Alzheimers, but if it is a lot more than cancer for example, then it might be decades or more away from being well understood.
I hate to say it, but cancer and HIV feel more like things we can get, Alzheimers feels like something only old people get, and it's to easy to forget that we'll get old, and it's hard to think our older loved ones might be affected. If no one in your sphere has been affected, it's harder to prioritize the disease.
My opinion is, money is the biggest obstacle, and I don't mean money for research, but money for education for researchers, and the talent pipeline. If higher education (at least for medicine) was literally free, that'd be a start. then you need lots of people getting paid to do the research independently. Right now, it feels like most disease research is being done by big pharma, so they can find the next insulin they can use to maximize profits. The incentives are all wrong on all sides, for potential researchers, the public and R&D companies.
I can't see why HIV treatment would generate more profit than dementia, that doesn't make any sense to me. Dementia affects a lot more people, and it affects the wealthiest possible demographic. What is your logic there?
> Nonfamilial early-onset AD can develop in people who are in their 30s or 40s, but this is extremely rare, and mostly people in their 50s or early 60s are affected.
Depending on what you consider "old", this might not change much
An old friend of mine was one of the people working on this. Had access to top10 supercompute time and everything. He never wanted to talk about it, and he'd talk about anything. Said it made him see red. Not long before the news broke, he killed himself.
I'm pretty adamant it was fraud. You don't have to look very hard to see how profit incentives are fucking up the health/medical sector. Check out how often $1000+/dose drug goes generic and within +/- 3 months a study is published that reveals it can be strongly linked to any number of issues that would have caused it to never get approved in the first place. Then you look at the original studies and see they specifically excluded anyone that those problems would have shown up in!
...because Alzheimer is a dormant side effect of a virus, not of a messenger chemical. But that doesn't go well in studies and "self populism" of what funded research wanted to hear.
If you study effects and not causes due to lack of measurements for reproducibility in any field of research, that's what comes out.
Also check out how the new and promising correlation started by observing the Wales eligibility for mandatory shingles vaccination during an outbreak and the effect on that test group when it comes to alzheimer or dementia in their old age.
Note that shingles (herpes zoster) virus is a dormant virus for decades, and it's not really treated because of that.
Also note that this was only discovered because people died and their data set was publicized because of that, which I hope that can happen in an anonymous way due to it being invaluable for medical research.
That's why I was emphasizing "one way" and "can begin".
Clearly viral infection may be a distal factor but it is not the proximate cause of Alzheimer's... which is quite conclusively due to protein aggregates.
Yes, exactly. Whether it APOE mutation, traumatic injury, metabolic dysfunction, Herpes infection, or some other inflammation that upregulates kinases, you end up with hyperphosphorylated tau which in turn forms the neurofibrillary tangles that destroy nutrient transport in neurons and eventually kills them.
"Neuron death by protein aggregates" is the best way to define Alzheimer's. Anything more specific refers to only one of those aforementioned causes; anything less is just "brain don't work no more."
These clickbait headlines are so frustrating, especially since the article itself explains the tau mechanism and all the progress that has been made in understanding the disease.
It very much has been. Which is why it's tiring to see these articles (and HN comments) portraying it otherwise. Search HN for Alzheimer's and you will find lots of updates on the research and lots of the same uninformed comment threads.
... which kind of points to the indicator that "Alzheimer != Alzheimer", implying that too many diseases with the same side effects are categorized together?
A lot of virological and parasitical components have historically been wrongly associated with genetic markers, too. Toxoplasmosis parasite comes to mind.
I am not a researcher in this field. I have read a lot about APOE4, and nearly everything I have seen about APOE4 makes it out to be the clearest of all predictors for Alzheimer's. I get that you're upset that I posted like I did, but I am not trolling. The point was that genetic causes are not an exceptional predictor for Alzheimer's. I had a hard time seeing how the best established predictor for Alzheimer's validates there being too many things labeled as Alzheimer's. If I had posted with a focus on some edge case, then it probably would have made more sense to me, but as I read it, it really seemed like a stretch.
Dropping this thread now. I am fine with being wrong, but my brief posting was not trolling.
Most of these comments are spot on. We seeded (and continued to fund) the most recently approved Alzheimer's drug on the market about 15 years ago and fought an uphill battle the entire way. The entire industry - other than what seems about a dozen neuroscientists - were fully bought into the plaque scam, and many still are. As I mentioned in a different thread some time ago, the best way to think about plaque is like gravestones in a cemetery. If you remove the gravestones, the dead bodies are still there.
We were introduced to the head of neuroscience at Houston Methodist as part of our due diligence process; his entire career was built upon the removal of plaque from the brain and would not even consider an alternative theory. We ran into this for years. It made funding the trials very difficult. We were totally ignored by all the Alzheimer's charities and orgs (ie Seth Rogan's for example). Only the Michael J. Fox foundation contributed early on.
However, our drug, now known as Zunveyl, was a pro-drug of already on the market Galanatmine, which was the second most commonly prescribed drug in the world for this disease (about $6BN/yr). Our pro-drug almost eliminated the side effects of Galanamine (nausea, vomiting) and enabled us to increase dosage high enough to actually get enough molecules into the brain. It was (is) awesome. Some of our first clinical trials were healthy young adults - they did extremely well. I don't think I can share the actual results but I hope that we (or someone) can fund a study to get approval for "regular people" usage one day given how well this test went. Later tests went just a well but only thanks to the "fast track" program were we able to even get to market.
Even today after being on the market for about a year now, the market uptake is slow due to insurance company approvals. We are getting reorders like crazy but often new patients get denied initially and then doctors have to appeal and then they get approved. This has been taking about 6 months on average and is brutal for people with the disease (and their families). Since getting a drug to patients is actually a (sadly and surprisingly) large sales and marketing expense, the company (Alpha Cognition) is focusing on long-term-care centers for now, but we had always hoped that this would be available much more broadly and much faster. Several of the early investor's parents were alive and afflicted with this disease when we started, but have since passed away. I hope that we can get this out and help others - faster.
The mother company that spun this out is also working on other molecules to try to stop Alzheimer's itself, rather than "only" help with symptoms but as always funding is a challenge. Clinical trials must be done correctly and are thus expensive.
Been living this battle for 15+ years and hoped that this can shed a little light on how things have been.
Same scam and politics as the Ancel Keys lipid-heart hypothesis. Complete BS, ego and career protectionism, resulted in the deaths of millions and most people still believe that crap.
Ok so how does he know that? This whole podcast is about how we don't even know how tau clumps and amyloid build ups relate to the progression of the disease.
Now that the “plaques are the disease” folks are having to listen to viable research in contradiction to them, there is a possible outcome that an mRNA vaccine for tooth decay ais also an mRNA vaccine for Alzheimer’s, if that particular theory pans out. Which would subtract a trillion dollars from GDP over a medium timescale. I remain hopeful :) but I’m not particularly holding my breath for the U.S. to invent a cure at this point, simply because of how much profit it will cost the booming industries of health insurance and elder care.
Do you have a link? A biotech company called Cortexyme already tried a drug against P. gingivalis, which causes gum disease, based on the idea that these bacteria migrate to the brain (many old people who died of AD have gum disease and tooth loss). But that drug failed phase II/III as there was no evidence of any effect.
Big Pharma refuses to believe that the gut microbiome plays a significant role in human health. They either don't take it seriously or think it's so complex that it's not worth working on. I think they're totally wrong and that the microbiome is the arbiter of not only Alzheimers but cancer and other metabolic disorders like T2 Diabetes.
Regardless of what you believe, the idea that big pharma doesn't believe in gut microbiome playing a significant role in human health is absolutely wrong as easily seen by the rise of GLP-1 drugs (which affect gut microbiome) and are the blockbuster drugs "big pharma" is investing heavily in currently. Perhaps, go take a look at that.
What are the 3 pro’s of Alzheimer’s disease?
The 3 pro’s of Alzheimer’s disease are:
- Every day you make new friends
- You can hide your own eastern eggs
- And every day you make new friends
——-
This a a bit of a dark joke that goes around in The Netherlands. In Dutch it goes like this:
Wat zijn de drie voordelen van Alzheimer?
De drie voordelen van Alzheimer zijn:
- je maakt elke dag weer nieuwe vrienden
- je kan je eigen paaseieren verstoppen
- en je maakt elke dag weer nieuwe vrienden
—-
The meaning of this joke is not to ridicule patients whom suffer from Alzheimer’s disease. Not at all. It is just meant to make people smile for just an instant. And making them experience a little how Alzheimer’s can affect your brain.
About the question: Alzheimer’s disease is a condition of the elderly, and they’re on their way out anyway. That is what I observe. Healthcare is a moneymaking business. In capitalism. While it should be free. And excluded from patenting or copyrighting. Healthcare has turned into wealthcare. No wealth? Game over. No extra life for you.
On the other hand, maybe the subject is just so complicated for today’s scientists. It is all in the eye of the beholder. The existence of F1 racing cars doesn’t mean that Tesla will never be part of Formula One’s future. As we speak there’s already one Tesla racing through space…
"Alzheimer’s disease is a condition of the elderly, and they’re on their way out anyway." That's a such a protestant way of thinking. It contrasts very much with the catholic culture of southern Europe.
I am not saying that is better or worse, but I think it is a very clear example of how different the culture is across the UE. One key aspect is how to look after your elders.
I might sound like a broken record, but dentistry is stuck in the past.
Alzheimer's is basically an advanced form of gum disease caused by Porphyromonas gingivalis) that has infiltrated into your jaw and then traveled into your brain where it causes systemic inflammation which in turn lets other pathogens in that cause neurodegeneration.
There is probably no cure because the only thing you can do in dentistry is prevention and preventative dentistry is still in its infancy.
This is probably wasted on the HN crowd though, because I haven't seen any demand for preventing Alzheimer's.
The company I work at has been building a dementia prevention program covered by most insurance plans in the US.
Our clinicians work directly on helping understand risk of neurodegenerative disease and help tailor personalized plans to improve outcomes.
A recent lancet study concluded that around 45% of dementia cases are preventable [0]
Happy to answer any questions people have.
Different person, unrelated to the above advertisement but:
Sometimes any diet.
Mental health struggles can exacerbate, (and be exacerbated by!) forgetting to eat, not wanting to eat,
forgetting or passing up the things that keep you in homeostasis, choosing the less correct things because of an emotional response, a physiological response in a “diminished” state.
I asked because I already know the correct answer, which is "metabolic psychiatry", meaning versions of keto/carnivore/epilepsy-keto diets (the latter is the strongest).
I have a kind of outlandish hypothesis that needs more research before it can be taken seriously, but it basically says that the cause and effect are backwards. Mental atrophy due to less learning/thinking, isolation, loss of meaning and purpose happens first. The sleep down regulation and decay of mental circuitry comes after. Would explain why treating the physical symptoms doesn't work.
Protective against the problem is anything which keeps you mentally active, such as socialization, work, religious community participation, hobbies, and meditation. Retirement, death of partner, isolation, sleep deprivation, depression, dissociation, psychosis, medications/drugs which interfere with restful sleep increase risk.
A possible falsification of this hypothesis would be if it's caused by inactivity or physical self neglect, as those often go hand in hand with the correlated and anti-correlated factors mentioned above.
This is particularly interesting:
> Intriguingly, studies show conscientiousness and neuroticism to be associated with Alzheimer’s disease and related dementias but not with their pathologic hallmarks such as plaques, tangles, infarcts or Lewy bodies in the brain.
I mentioned this could be a possible falsification of the idea. It's also possible there are multiple causes and the modality I mentioned is a cause for some. I'm not sure. There are definitely cases where isolation contributes to cognitive decline.
Exactly. My mom lost her job because of early onset. She was very social, read tons of books, etc…. Now, I’m happy she at least still knows who am, but she can’t put a sentence together.
A hypothesis is an unverified tentative insight into something which could be true. Current research is correlating dementia with a wide variety of areas including even personality typologies which are nothing more than statistical clusters of observations.
What I did when I stated this is looked at a number of observations from current literature and asked a what-if question. People unwilling to ask these questions are blinding themselves to entire areas of possible explanations. My hope when posting this was that people might engage with the idea instead of calling it a guess. Retirement, isolation from pandemic lockdowns, isolation from solitary imprisonment, and isolation from death of a partner are all associated with cognitive decline.
There's enough correlation here that it would be worth researching. That's all I am saying, I am specifically not saying my claim is factual just that it is a possible explanation that if true would explain a lot.
Its done substantially better than more common diseases like ME/CFS which very few have even heard of let alone know the symptoms of and receives almost no funding at all. Alzheimer's received a further $100 million of NIH funding earlier this year (https://www.alz.org/news/2026/100-million-dollar-alzheimers-...). That is 6 times the total funding for ME/CFS federally which is currently just 15 million and planned to decline.
The research went awry in Alziemer's due to fraud but its being funded at a reasonable level, a level many with Long Covid or ME/CFS or Fibromylgia would be very happy to see but doubt will ever happen. Funding of diseases is not "fair", it isn't based on number of sufferers * quality life years lost and we should be spending more on medical research generally. Alzeimers is one of the better funded diseases in the world.
> long COVID is probably more accepted as a real thing by practitioners at this point than CFS
Isn't long covid just CFS that can be attributed to Covid?
If you accept that multiple viruses can cause "long <virus>" syndromes, of which long covid is just one example, it's plausible that CFS is really a cluster of syndromes, one category of which is these post viral syndromes. We just can't pinpoint the virus behind it every time because most viruses haven't been studied as much as Covid has.
It is understandable for being downvoted in an off-topic discussion about ME/CFS in an Alzheimer's hacker news post.
But I believe the reason he is getting downvoted is because much of it is objectively incorrect, and people who live with ME/CFS don't have energy to go in depth to give a detailed reply.
I appreciate your interest in this topic, but respectfully, many of your points are incorrect.
ME/CFS is real. [1][2][3] Alzheimer's is terrifying, but I don't believe it is fair to say that it is obviously more terrifying than ME/CFS. People with ME/CFS have an abysmal quality of life. [4][5] And finally, ME/CFS is significantly underfunded by an orders of magnitude across all metrics, even when you account for the some of the concerns you raised such as dollars per patient, dollars per year lived with disability, etc. [6][7]
For those who haven't heard of ME/CFS, let me give you a high level summary.
We are all fatigued in this day and age, but fatigue isn't sufficient to describe what it is like living with ME/CFS.
At mild severity you are so fatigued that you have to decide between showering or doing laundry as your one physical activity for the week. But if misjudge and overexert yourself, it can take days or weeks before you get some of your energy back, assuming it ever does. Overexertion risks permanently decreasing your energy capacity.
As ME/CFS progresses in severity, the more comparable your life becomes (subjectively) comparable to someone with Locked-in syndrome. You become unable to talk and walk. Even looking at colors and hearing loud noises can be too much exertion, leading many people to wear earplugs and blindfolds for all hours of the day for months/years at a time. You have no choice to lay unmoving in bed all hours of the day with nothing but your limited thought capacity to keep you company. ME/CFS is currently incurable and virtually untreatable, but usually isn't fatal. It is possible that the disease eventually gets so severe that breathing and beating your heart is too much exertion, but that is almost unheard of. You have to live like that for rest of your life.
You are surrounded by people who don't even believe in the disease, and getting disability benefits is borderline impossible.
This disease isn't even rare - estimates are between 1-3 million people in USA alone. That's roughly 1 in 100 to 1 in 300.
They had a biological model. They had multiple drugs that were showed activity against that model, and effectiveness in humans. Problem was, the model was wrong. Pharma’s burned billions chasing this as it’s possibly the biggest market imaginable.
Whether it was fraudulent or just incorrect is a different question. We don’t know all of the details of human biology. We don’t even know what all we don’t know. Most guesses work to some degree to keep pharma alive - otherwise nobody would fund the business.
Edit: Google the in the pipeline blog. This and other have discussed this at length.
> Problem was, the model was wrong.
I thought despite the fraud, it's still the best model we have[1]? The fact there was fraud doesn't mean the model is immediately incorrect. At best, it means its foundations are shakier than we thought, but it's not a slam dunk repudiation.
[1] https://www.astralcodexten.com/p/in-defense-of-the-amyloid-h...
Pretty clearly not. It would seem that beta amyloids correlate with Alzheimer's, but do not cause it.
The problem us "consensus science". You could get funding to research beta amyloids, but not to research any competing hypotheses.
It's much like climate science today: any dissent at all, even just questioning the predictions of catastrophe, immediately brands you as a heretic.
> It's much like climate science today: any dissent at all, even just questioning the predictions of catastrophe, immediately brands you as a heretic.
I'm not sure I understand this. We've added hundreds of gigatons of carbon to the atmosphere. There's no mystery here, it's basic physics and chemistry that this will change things, and it's accepted that we don't know exactly _how_ things will change. The alternative: "adding gigatons of carbon to the atmosphere will _not_ change anything" is simply non-sensical. It goes against the basic rules of physics and causality. I'm happy to be proved wrong here, I just legitimately can't see how an alternative position makes any sense.
Edit: I see you specifically pointed out "predictions of catastrophe", which if that is true (and not just the position of radicals on Twitter) is indeed unfortunate.
Yes, there is overwhelming evidence of climate change. And that we are causing it.
However research into what we humans can do to ameliorate it is verboten. For example https://www.scientificamerican.com/article/fertilizing-ocean... was an actual experiment that found a low cost way to both remove lots of CO2, and improve a fishery. But that line of research has been shut down.
Likewise research into the current impact is only allowed if it agrees with what is politically correct. For example many researchers have found that current severe California forest fires are mostly due to poor past policies, that have resulted in very dense forest, with a large fuel overload. But research that stresses the impact of climate change are easier to publish, and this shifts the apparent consensus on the causes of things like the major 2025 fires in the Los Angeles area.
From your link:
> Not geoengineering
> The project is also unlikely to bury much if any carbon dioxide for one simple reason: metabolism. As other iron fertilization experiments have shown, it is relatively easy to get plankton to bloom, but it is harder for that bloom to sink to the bottom of the ocean, where it takes CO2 with it.
This project is a net carbon emitter by design.
Do you really think that adding iron releases net carbon? That would be hard to explain chemically.
The worst case scenario laid out in that article is that most of the carbon absorbed, was later rereleased. So net zero carbon, not net carbon emitter.
I've seen other reports of that exact experiment that estimated a significant net carbon sink. The actual experiment failed to make measurements that lets us know which actually happened.
Regardless, we've certainly demonstrated that, at least sometimes, there is significant net carbon capture, at low cost. Given the certainty of global damage at present, I believe that this justifies continued experimentation. Even if it means accepting possible risk to local ecosystems. The local ecosystem can generally recover. The planet, not so much.
You think the chemical compounds were just magiced into the ocean with no carbon intensity. It literally says carbon will not be absorbed and that geoengineering is not the goal.
Climate science is much more complicated - there are many things you could disagree with beyond will tons of carbon change things, yes or no.
Like are we doomed or will it just get a bit warmer before we switch to solar for example.
There are also money issues like with the alzheimer's situation. If climate change is dooming us then we should send more money to climate scientists.
> There are also money issues like with the alzheimer's situation. (that is: If climate change is dooming us then we should send more money to climate scientists)
Absolutely, the issues are similar
And if this can upend the business model of some big companies we'll give some "incentives" to some "doubtful" scientists even if their doubts are unfounded (actually very well founded but you get the gist)
Which sucks because such work should be free of pressures and incentives
> we should send more money to climate scientists.
Couldn't disagree more.
Please spend it on those who might actually fix something. There's plenty of can remove carbon or can undo the effect of X on Y. Let's stop falling back on the bad argument of we must leave nature alone right after arguing we change billion dollar industries because we can.
We shouldn't learn to be custodians watching the planet die because of past mistakes, we should be fixing and improving the planet and improving on nature because we can, must and should, shoulder this reaponsibility.
Please not _yet more modelling_ burning HPC into the ground just for a crappy bar line graph (based on assumptions)...
> we should be fixing and improving the planet and improving on nature
How do you do this without a process of finding out what works and what doesn't? Isn't that science? Or am I misunderstanding you saying no more modeling to mean we already know everything we might need to know in order to shoulder this planet scale responsibility and just collectively aren't doing anything except making bar charts?
What does your proposal actually look like without science or climate modeling?
Actually my "Absolutely" referred to the first phrase, not the second one (my bad!)
> If climate change is dooming us then we should send more money to climate scientists.
Depends! If you're a large fossil fuel company, the obvious move might be to spend more money on advertising agencies scientists, or entire foundations who question climate science instead.
... which they did. https://link.springer.com/article/10.1007/s10584-013-1018-7
Meanwhile, the basics were known since the 19th century. https://www.rsc.org/images/Arrhenius1896_tcm18-173546.pdf
I am baffled by the number of people on HN, presumably a website for and by technical people, who fail to consider secondary and tertiary effects when it fits their worldview to do so.
There is a yawning abyss of states in between extinction and 'boy sure is a few degrees warmer out here' and none of them are good.
Many organisms would benefit from a warmer climate, just not humans.
We rely on extremely narrow conditions for the fragile supply chains and power structures that keep us on the ragged edge of civilized to continue working. We had an extremely mild contagious disease outbreak, by historic standards, and our economy is still feeling the effects!
Imagine the impacts of something like wildly different rainfall patterns, increased rate of global infectious disease, shifted agricultural zones, changes to Jetstream patterns, large scale crop failures, loss of water supplies, temporary local ecosystem collapses etc. These changes are incredibly fast on the scale of what it takes to reach ecological equilibrium.
These of course mean nothing to biological life, writ large. Life will recover and adapt. To fragile human civilization they mean refugee crisis, resource wars, failed infrastructure, and ten thousand other existentially terrible things.
I get your point but on the other hand humans live quite well in places like Medicine Hat say where it swings from -40 C in winter to +40 C in summer. Against that the likely warming by say 2100 is I think 1.5C up from what it is today which might be just about noticeable?
Did you read the post at all? Second order effects, not primary effects. Its exasperating how much effort people will put into not understanding the smallest things when they are inconvenient to their worldview.
> Many organisms would benefit from a warmer climate, just not humans.
and a whole fuckin lot that wouldn't, and that may collapse the ecosystem
> There's no mystery here, it's basic physics and chemistry that this will change things, and it's accepted that we don't know exactly _how_ things will change. The alternative: "adding gigatons of carbon to the atmosphere will _not_ change anything" is simply non-sensical. It goes against the basic rules of physics and causality. I'm happy to be proved wrong here, I just legitimately can't see how an alternative position makes any sense.
With any position, you have to distinguish between its thoughtful advocates and its thoughtless ones-every position has both
Any thoughtful “climate change sceptic” is going to say (a) of course the climate is changing-it always has and always will; (b) of course it is implausible than human activity has literally zero impact on that change. But that still doesn’t tell us: (i) the relative scale of anthropogenic versus natural causal factors; (ii) the validity of any specific predictions of future change; (iii) the likely socioeconomic impacts of any future changes that may occur. It is totally possible that a person may affirm (a) and (b) while questioning the “consensus” on (i) and (ii) and (iii)
Personally, I don’t have a strong opinion on the substantive issue - but I wonder about the extent to which mainstream discourse on the topic represents good epistemic hygiene. It is even possible that the sceptics are on the whole more wrong than right, but simultaneously the mainstream response to them is more irrational than rational.
Yes I believe GP was focused on the catastrophe part. It's very likely correct that our CO2 emissions are warming the atmosphere ocean etc, but it's not clear that runaway warming is inevitable or that life or geology have feedback mechanisms that turn an exponential into an S curve. That is, after all, basically what natural selection tends to do. Turning the table again, even if there are corrective factors humans might have immense suffering before it stabilizes. So we don't know.
You didn't ask, but my opinion on it is that we'll probably stabilize on a cleaner energy source and find natural countermeasures when suffering ticks up. Any top down pressure to change things whole cloth seems doomed, no matter how benevolent. We're closed loop creatures.
> but it's not clear
What better way to find out than to just try it and see if we end up with runaway warming? That surely can't cause any harm.
The analogy isn't a perfect one.
For Climate Change it's a question of opportunity costs. With expected inputs how much will temperature change? What are the effects of that change? How much effort to you put into changing the inputs? How much effort do you put into dealing with the effects?
The biggest difference is that Climate Change is a deeply political question with a bit of science tossed in. Alzheimer's is the mirror opposite - it's a scientific question with politics added to the same degree of most other things.
[dead]
[dead]
> It's much like climate science today: any dissent at all, even just questioning the predictions of catastrophe, immediately brands you as a heretic.
I think this is not a great example, as there’s a huge group of people that, in fact, does not agree with the consensus and would happily fund research that (tries to) prove otherwise.
I fully agree with your point, though, just not the example.
That’s not true. If you want to have a job at a prestigious institution then the research committees are pretty consistent in their biases.
The comment you were replying to was talking about funding. If you could develop a scientifically plausible model to defend the "burning fossil fuels is not so bad, actually" thesis, your funders would include the oil companies and the greater petrochemical industry. There is a lot more money to fund projects there than... anywhere else in the world, really, by a wide margin.
well oil companies funded "lead fuels are safe" research...
...and it really did backfire (in public relations, politics, etc)
now... I don't think they can actually fund 'research-for-their-profit' -- I mean, would you believe "petro is good for earth" research coming from oil companies, even after the 'lead is good or neutral' research?
Yes.
Not uncritically, but if the research presents a logically consistent hypothesis, and evidence supporting it, then it would be worth following up on with independent groups and if it remains consistent to scrutiny then it should be accepted.
That's how science works.
There are so many counterexamples proving that your statement is just not true. I'll give you just one example, the Berkeley physics professor Richard Muller that took funding from the Koch foundation to attempt to "prove" that the satellite temperature data was "miscalibrated" and estimates of actual warming were overblown. Started the project in 2010. First published in 2011 showing that in fact the warming was real and using more advanced calibration techniques actually showed the warming was worse than we thought.
Expecting scientific rigor is not a bad bias: everyone who has been willing to do actual science agrees that climate change is real and significant. For example, Richard Muller was a climate skeptic who had a great job at one of the most prestigious universities in the world, got funding to establish a team to critically review climate science research … and concluded it was right:
“When we began our study, we felt that skeptics had raised legitimate issues, and we didn’t know what we’d find. Our results turned out to be close to those published by prior groups. We think that means that those groups had truly been very careful in their work, despite their inability to convince some skeptics of that.”
https://www.nas.org/blogs/article/after_climate_research_phy...
If you haven’t read up on both, it’s hard to appreciate how unlike climate science is from the beta amyloid theory. The latter has some evidence but there were always alternate theories by serious researchers because it involved multiple systems which scientists were still working to understand and basic questions around causation and correlation had significant debate.
In contrast, climate scientists reached consensus about climate change four decades ago and by now have established many separate lines of evidence which all support what has been the consensus position. More importantly, since the 1970s they have been making predictions which were subsequently upheld by measured data from multiple sources. The ongoing research is in fine-tuning predictions, estimating efficacy of proposed interventions, etc. but nobody is seriously questioning the basic idea.
Almost all of the people you hear dismissing climate change are funded by a handful of companies like Exxon, whose own internal research showing climate change was a significant threat produced a chart in 1982 which has proven accurate:
https://skepticalscience.com/pics/Exxonpredictions.png
https://insideclimatenews.org/news/16092015/exxons-own-resea...
having worked in amyloid, and in an a-beta lab in the second half of the 2000s, we always said under our breath in group meetings that we were skeptical about the amyloid hypothesis, but our grant applications certainly did not say that (or if they did it was a quick throwaway sentence). And I think the lab that I landed in was one of the most honest scientific labs in biochemistry/chemical biology.
Over the past decades the group that are not happy with the AGW consensus in the hard earth sciences crowd have principally funded FUD via think tanks, ala the pro-tobacco lobby back in the day, rather than research.
The few examples of research driven from the skeptic PoV (eg: urban heat skewing, etc) have landed on the side of the AGW consensus.
And when they funded research, it confirmed the known science.
https://www.scientificamerican.com/article/exxon-knew-about-...
If anything the current consensus on the scientific front lines is that the alarmism is understated, and the real orthodoxy is astroturfed denial of the facts.
The global fossil industry is worth around $11 trillion a year. It supports some of the worst regimes in the world.
Of course they're going to try to FUD away the science, with the usual copy-paste narratives about how it's really scientists and academics who are corrupt.
It's all about money, power, and entitlement. Not about truth or responsibility.
But no amount of PR nonsense, astroturfing, and false accusation is going to make the slightest difference to climate reality.
half the stuff currently in clinical trials is not targeting amyloids.
https://alz-journals.onlinelibrary.wiley.com/doi/10.1002/trc...
[dead]
> It's much like climate science today: any dissent at all, even just questioning the predictions of catastrophe, immediately brands you as a heretic.
The financial motivation for fraud is all on the side of climate-change denial. Literally trillions of dollars of motivation.
Hah! What do you call the cap and trade group? The whole trillion dollar "carbon credit market" is a farce built to profit from climate change catastrophism.
You are mistaking the beneficiaries here. Carbon credit scheme is indeed a greenwashing scam and it is pushed by the oil and gas (plus adjacent) industries. It is plainly obvious that shuffling emissions between jurisdictions does jack shit against reducing the actual real amount of emissions to the atmosphere. Basically the main proponents of the carbon credit fraud are the same people financially motivated to reject long term climate change consequences (aka anti-"catastrophists" in your lingo).
If cap-and-trade held the same levels forever you would be correct. But all of the cap-and-trade systems I am aware of have a built-in lowering of the cap over time. So they start out doing nothing/very little, then ramp up to meaningful reductions over time.
The idea being both to make it easy to get people to agree today (the reductions are tomorrow's problem), and to allow time (and foresight) for industry to adapt to where things are going.
Small change compared to global fossil fuels. Energy (which is still mostly fossil fuels) is 10% of the world GDP.
Climate-change denial is just like tobacco-cancer denial. It's the same banal "I win, you all lose" mechanism. Enormous resources are available (along with the useful idiots) to propagate falsehoods.
"Consensus science" is science.
Yes, though when the consensus doesn't work for predictions then it is a matter of time until it stops being science.
A degenerating research programme.
Not by my prefered definition. I like science being the study of nature through reason and experiment. Reality trumps consensus.
>> It's much like climate science today: any dissent at all, even just questioning the predictions of catastrophe, immediately brands you as a heretic.
Nonsense. It is actually quite unlike climate science, where the consensus of catastrophe and the evidence for it are both overwhelming. Dissenters are listened to only to the extent they can provide overwhelming evidence to the contrary, which they so far cannot.
The problem is that the top researchers in the field have spent their lives devoted to amyloid beta. They may well have helped direct hundreds of millions in grants to this line of research.
The idea that they have blocked the treatment of Alzheimer's rather than helping it, is very, very painful. This is perfect for creating cognitive dissonance.
And so, no matter what the evidence, they remain committed to the conclusion.
As a result, the latest Alzheimer's drug to enter stage 3 FDA trials is Trontinemab. (It is currently in stage 3.) It targets the amyloid target.
A relative drop in the bucket is going to, say, the infection hypothesis. This despite the fact that the only intervention that has been shown to reduce the incidence of Alzheimer's, is the shingles vaccine.
>I am David Schneider-Joseph, an engineer formerly with SpaceX and Google, now working in AI safety. Alzheimer’s isn’t my field
If anyone wants to know who wrote the article linked before wasting time reading it, there you go.
Many in this thread, who have evidently spent very little time studying the topic, have confidently concluded the experts are wrong.
I, also a non-expert, spent six months studying what the experts are doing, concluded that they actually seem to know what they’re talking about, and shared my understanding of that with other non-experts.
If you’re going to dismiss me for saying the experts are right, since I’m not an expert, then shouldn’t you dismiss those who spent far less time than I to learn about the subject, who are saying the experts are wrong?
DSJ! I remember you from about 2001, when you had made the chatbot VIAL. I can vouch for you being a smartypants 25 years ago, don't know about now.
Ha! You must be using a different username than I knew you by then. Hit me up on one of the many platforms we’re probably both on if you like, would be good to reconnect.
>then shouldn’t you dismiss those who spent far less time than I to learn about the subject, who are saying the experts are wrong
Already have
For you, simply listing the author of the post is enough to discard it. Not everyone is that well informed, so it would be helpful for you to add another sentence explaining why this author has no credibility with you.
It is self-evident? What do you mean. The guy is not an expert, end of story
By this logic, we wouldn't have some of the breakthroughs made throughout history. Outsiders have made some pretty interesting leaps (later honed by experts). Expertise is great, but it can exist outside of formal education, and it isn't the only metric.
Might this be a doctor vs. physician assistant situation?
The people who know the most are probably busy and (not to be rude) are not necessarily the strongest educators.
Maybe my standard is too low here or I have a different need than you, would make a different accuracy-accessibility tradeoff…
there is even easier way to estimate the chances of time wasting - it is a "rationalist" website, an "effective altruism"-like version of rationality.
wrt. original post - quickly googled, and that for example https://www.news-medical.net/health/What-are-Amyloid-Plaques... - pretty short and seems to be clear that amyloids do have some correlation while may or may be not the cause.
"Amyloid plaques form one of the two defining features of Alzheimer’s disease, the other being neurofibrillary tangles"
Interesting that the latter is inside the neurons while the former is outside - speaking of complexity. The article also describes that activating microglia back helps with amyloid plaques while this
https://pubmed.ncbi.nlm.nih.gov/33010092/#:~:text=The%20stud...
"The neurofibrillary tangles (NFT) and amyloid-ß plaques (AP) that comprise Alzheimer's disease (AD) neuropathology are associated with neurodegeneration and microglial activation. "
Human body reminds a large monolith codebase - fixing one thing breaks some other :). Claude Code, Human Body CRISPR edition, can't come soon enough...
>there is even easier way to estimate the chances of time wasting - it is a "rationalist" website, an "effective altruism"-like version of rationality.
Is that supposed to be an endorsement or a dismissal? The ostensible goals of "rationality" seem like good things, so it sounds like an endorsement, but in the wake of the FTX/SBF fallout they got a bad rap.
there is a big difference between a theory/idea and espousing the theory/idea as an ideology.
Huge codebase with years of fixes, features and hacks added on top and nothing ever refactored.
It’s a miracle it works at all
It is worse. The code changes are mostly random, only surviving the tests of fitness nature is applying (on various levels though; immediately catastrophic changes on level of cell biology are sorted out). And at least the high-level tests are also random and unreliable.
So basically it's a codebase mostly composed of bugs, and the features mysteriously work because they're based on bugs that happen to be mitigated by other bugs. :)
A billion years of kludges.
Many in the research community realised the model was wrong a long time ago. This is a great read about the reasons why: 'How not to study a disease: the story of Alzheimer’s.' by Karl Herrup.
Wrong or incomplete?
The current findings seem consistent with "both plaques and tangles are significant components of the pathology" and "our interventions are typically late and the accumulated neurological damage is already extreme by the time clinical symptoms show".
Attacking the plaques wasn't completely worthless - findings show that this often slows disease progression, especially in early cases. There are pre-symptomatic trials ongoing that may clear the air on whether "intervention is late" is the main culprit in treatment underperformance.
the model is wrong, but the amyloid is still sitting there, staring at you, asking you what are you going to do about it?
It's a classic example of "correlation does not imply causation". It was indeed observed that some patients with neurodegenerative conditions do indeed have amyloid plaques. It was further observed that patients with known Alzheimer's do not necessarily have amyloid plaques and patients without it do have plaques. The existence of amyloid plaques itself or the level, apparently, correlates extremely poorly, if at all, with the existence, onset or severity of the disease. Drugs attacking amyloid plaques might work, but they don't reverse the disease and do very little to slow progression. That's all scientific observations.
> I thought despite the fraud, it's still the best model we have[1]?
It is observed that one of the features of neurodegenerative diseases is decline in glucose metabolism. Supplementing energy availability (e.g. ketones [1], creatine [2]) does improve symptoms in patients with wide variety of CNS diseases, including Alzheimer's, senile dementia, epilepsy, and migraines.
The ATN model you have linked might as well be just ONE OF possible pathways to glucose uptake inhibition, which could be the causal pathology of the symptoms.
So no, it is very much not necessarily the best model we have. Inhibiting any pathway towards a disease is always a good thing, but the characteristics of "best" models are broad applicability and we have a serious contender.
[1]: https://link.springer.com/article/10.1016/j.nurt.2008.05.004 [2]: https://alz-journals.onlinelibrary.wiley.com/doi/full/10.100...
A wrong model is not the same thing as fraud, and biology is full of plausible models that later turn out to be incomplete or misleading
While true, there are a bunch of very influential results in Alz science that turned out to be fraud.
The Amyloid hypothesis persisted for so long because we didn't have any obvious counterarguments since it is so hard to do studies on the brain. Which also means that it's not a bad hypothesis.
What happened is we got the tools to start studying viral associations with other diseases and ... whooops ... suddenly there are associations. The shingles and RSV vaccines seem to affect dementia while others like influenza don't.
Now people can ask questions about why those particular vaccines affect dementia while others don't. And suddenly we have falsifiable tests.
Now we can subject all hypotheses (including Amyloid) to stronger scrutiny.
There were no cointerarguments? There was a very simple counterargument: where was the causal data? If none exist why should I counter argue when you hadn't proven it to begin with.
There is a LOT of causal data. Autopsies of brains of Alzheimer's patients were rife with amyloid. People with mutations that caused amyloid got Alzheimer's earlier than others.
The hypothesis didn't come from nowhere.
To contrast, look at how much trouble medicine has had treating brain tumors. It has taken a long time to get effective treatments for various reasons. And Alzheimer's is way less direct in cause/effect.
> Autopsies of brains of Alzheimer's patients were rife with amyloid
Do you want think carefully about how this can possibly suggest this is a causal link?
> People with mutations that caused amyloid got Alzheimer's earlier than others.
People with mutations in those genes got a particular type of inherited alzheimers early, this says nothing about the cause of general Alzheimers.
> People with mutations in those genes got a particular type of inherited alzheimers early, this says nothing about the cause of general Alzheimers.
This is completely analogous to claiming that people with mutations in BRCA (which causes a lot of early breast cancers) says nothing about general "cancer".
That's simply flat-out wrong. Genetic mutations like BRCA affect certain subsystems and many of those subsystems are common and relevant to many different cancers outside of breast cancer or breast cancers that appear later. Lots and lots of cancer research proceeded by studying the common systems that BRCA affects. Sure, those subsystems aren't involved in every cancer, but they're involved in a solid chunk of them.
And, even better, when you find one that isn't affected by one of those subsystems that BRCA touches, that's an interesting result, too. Now you can look at what the differences are, figure out what the new subsystems are and categorize your cancer more specifically which makes successful treatment more likely.
There is absolutely no reason to believe that Alzheimer's is any different on that front.
Correlation is not causation but it's a pretty good idea to start with how blindingly obvious differences in brains affected with the disease might be related with the disease. There's also evidence that it precedes the symptoms of the disease.
And it's also not a good idea to suppose that you are dealing with unrelated effects without good reason. Mutations->more amyloid->earlier symptoms should be considered indicative of the disease pathway until sufficient evidence counteracts that, by Occam's razor.
Im not gonna try to correct you because its probably going to be futile, but I implore you to paste this thread into chatgpt and ask where you could be wrong in your logic.
Correlation not causation is all the more important in a topic like this; nothing you said suggests amyloid causes alzheimers or just forms because of it.
Just say your point instead of dancing around it.
What exactly do I need to say further? My first comment was that "scientists today still don't understand correlation =/= causation" and the replies are all scientists who try to explain again how correlation can still mean causation (no it doesn't, and it definitely doesn't in this case and that has been the root cause from the beginning). So I tried to implore you to go review your text yourself, but you are clearly above it, so not sure what else I could do here.
I would turn around the same request to you. I would ask that you look at how scientific research and hypotheses are actually created and the messy nature of evidence for anything that isn't particle physics and not just repeat cliches.
Research on the human body start with an observation, for the good reason that the omniscent orb has not invented yet, and what is causation and what is correlation is yet to be determined. Then, sometimes after years of research, it can be determined if what was observed was causation or correlation. That's why study that don't bring to a new discovery are extremely valuable nevertheless, as they show a path that was just a false lead and allow other researches to seek for something else
This comment is so needlessly aggressive and argumentative. I hate this about HN
It’s the way one talks to an LLM which has made a mistake.
It is also wrong...
Wouldn't mind knowing how.
It is sad. That reply, which you rightfully were irritated by, could have been expressed as a polite question.
That sort of question is what the response from user @bsder above helpfully tries to answer. That mode would invite more productive discussion, not more defensive annoyance.
Rules on HN say “Be kind. Don't be snarky. Converse curiously; don't cross-examine. Edit out swipes.” but it is hard.
All I can suggest is: be patient and try to be positive
Ah causal data! It’s a shame none of the scientists or statisticians thought of getting causal data. How would we get that? Well maybe we could just inject amyloid into a person’s brain. Or simply remove all the amyloid from a person’s brain. That should do it, right?
I mean an amyloid injection is wildly unethical and it’s also not the natural progression of Alzheimer’s. Removing amyloid is a simple matter of investing billions of dollars into drug development. Also how do you tell whether that was actually “causal” if the patients improve after plaque removal.
I mean come on, you have to work the evidence and the experimental tools that we actually have. This kind of epistemic puritanism doesn’t help anyone.
> Well maybe we could just inject amyloid into a person’s brain.
Erm, we kinda did? People who got cadaver-derived human growth hormone from Alzheimer's patients got Alzheimer's.
https://www.nature.com/articles/s41591-023-02729-2
And we just had an actual autopsy confirm a case: https://www.medscape.com/viewarticle/new-evidence-strengthen...
An obvious counter hypothesis is the amyloid is produced to counter an infectious agent. It is a reaction to that, not the cause. I think HSV-1 has been hypothesised. I'm not that up on it, just saying there are alternatives.
Which is only relevant if you actually find an infectious agent doing something in the right place, which so far we have not.
The vaccine prevention connection for example AFAIK is just pure statistics: you get the shingles vaccine, your population level Alzheimer's risk drops but we have no direct evidence of why this should be.
Its entirely possible we later find it has no effect and it's a population level quirk of people who were likely to get a shingles vaccine until that research - conversely the cost of just getting one is incredibly low (hence why I did, in relation to that exact data).
> Edit: Google the in the pipeline blog. This and other have discussed this at length.
Derek Lowe's blog is excellent, with 192 posts tagged "Alzheimer's Disease":
https://www.science.org/topic/blog-category/alzheimers-disea...
And, on a more entertaining topic:
https://www.science.org/topic/blog-category/things-i-wont-wo...
I miss Derek Lowe's "Thing I Won't Work With" series. I know there have always been large gaps between those posts, but it's been seven years since the last one so I guess they might be over. An excerpt from a favourite of mine:
"But I have to admit, I'd never thought much about the next analog of hydrogen peroxide. Instead of having two oxygens in there, why not three: HOOOH? Indeed, why not? This is a general principle that can be extended to many other similar situations. Instead of being locked in a self-storage unit with two rabid wolverines, why not three? Instead of having two liters of pyridine poured down your trousers, why not three? And so on - it's a liberating thought. It's true that adding more oxygen-oxygen bonds to a compound will eventually liberate the tiles from your floor and your windows from their frames, but that comes with the territory."
https://www.science.org/content/blog-post/things-i-won-t-wor...
Yeah; they had a wonderful earthiness to their language; both highly technical and highly vivid. Like this comment on hexanitroisowurtzitane:
> Recall that this is the compound whose cocrystal with TNT is actually less dangerous than the pure starting material itself, and yeah, I know that sounds like the guy at the pet store packing a starved Komodo dragon into the carrier with your new dog, just to calm him down some.
I'm guessing he just ran out of nasty chemicals. Either that, or he got tired of it and followed his muse elsewhere.
> Whether it was fraudulent or just incorrect is a different question.
And probably the more important question. How badly is the machine that does science broken? If we don’t focus here and fix it, there will be further decades without progress, all while wasting further billions.
> We don’t know all of the details of human biology.
Tautology statement. "We don't know all the details of X" for any X.
That is not a tautology. But you're right it's trivially true.
> In logic and mathematics, it is a statement that is true in every possible interpretation or situation.
... by definition
Tautology day is today because today is tautology day.
... not by "obviousness"
I can't check every stone for moss. We can't know every detail about anything.
> Whether it was fraudulent or just incorrect is a different question.
Sorry but good science should be reproducible an given the amount of major retractions around this field I think this starts to become more than a passing question.
Lots of work is built on top of the model which means a lot of money change hands and a lot of honesty hard work was done.
Those who built the bad model should be being asked why a) they were so wrong (bad conclusions are fine) b) their data was so bad (this is not defensible) c) they didn't push for reproducing their work sooner to support the field (more of a daming statement of a field which treats a statistical analysis as a push button tool)...
[flagged]
The peer review process was repeatedly cheated by self-serving fraud. The medical field requires honest results and reporting. Why are you defending the fraud?
Science is no longer a hobby for the idle rich, it's an occupation. Peer review cannot function in a hostile environment governed by self interest (results == resume). Science practice needs to adapt to modern conditions rather than to pretend the idealized system that worked for an exclusive and elite group would work for a competetive worldwide industry.
This is exaggerating and generalizing too much. Science still works extremely well in general.
For replying to me, can you skip to the part where you explicitly call out what you believe the cause may be,
as general of a label as it may be?
> We don’t even know what all we don’t know.
Somewhat ironic given the context.
> Pharma’s burned billions chasing this as it’s possibly the biggest market imaginable.
To be clearer, Pharma is chasing a nice long treatment plan, that will require expensive drugs till the end. Pharma does not heal - this is not good for business. So there are criteria around what they are searching for.
> To be clearer, Pharma is chasing a nice long treatment plan, that will require expensive drugs till the end. Pharma does not heal - this is not good for business.
This is a trope regurgitated by people who don't know any better. It would imply that pharma are deliberately avoiding research directions that would generate cures, or (even worse) discovering cures and putting them in a dark secret safe somewhere.
The reality is that drug development is serendipitous and really hard, and any company seeing even a sniff of a drug that works will throw everything behind making that drug a success. During the early stages of investigation of a promising new agent, the animal data can't predict much, and certainly can't predict whether something is "curative" - this would only be seen during human trials, after which hiding that benefit would be close to impossible. It's just not how it works.
There are plenty of examples of actual (rather than functional) cures being developed and marketed:
1) Previously-untreated DLBCL (a type of blood cancer) can be cured. CHOP chemotherapy cured ~35-40% of cases. The addition of rituximab boosted that to 60-65%. There then followed a long string of failed phase III studies (probably billions spent, cumulatively) trying to beat rituximab + CHOP, and finally in recent years there has been some success. So: multiple attempts across multiple pharma companies, trying to improve on an already impressive cure rate... not much evidence of an anti-cure conspiracy.
2) Hepatitis C - cures were discovered and marketed from ~2014 onwards; now ~95% of cases can be cured with a treatment lasting only a couple of months. So: multiple treatments, from multiple pharma companies, which offer a hugely effective cure for a pretty unpleasant disease.
I think you are wrong, for several reasons.
From the human perspective, researchers are people, and they do have their incentives. Making a breakthrough, of any kind, is important for them - even if for their career (but many do genuinely care and want to help humanity as a whole).
From marketing and sales perspective, look at what happen to pharma companies capitalization when Ozempic appeared: a relatively small Elly Lily suddenly got bigger then Merck, Novartis, Roche or Johnson & Johnson. You can hardly call it a long treatment plan with expensive drugs "till the end".
Really, there is a lot of bad things going on in healthcare and pharma industry, but the conspiracy theory "they don't want to invent efficient drugs" really makes no sense when you dig deeper.
I agree with you but Ozempic is a bad example here. Part of the reason it is so valuable is that patients usually must take it for the rest of their lives. Its actually the perfect example of “evil” pharma since patients slmost akways regain the weight if they stop taking it. This leads to dependence or people searching for grey market sources.
An example of “good” pharma would be Hepatitis C. We can now cure that. Although, pharma is charging the lifetime equivalent in order to do that (a treatment can run over $100k and insurance balks at covering it)
So pharma will absolutely develop a cure if they can. They however will still charge you as if you had to take a dose for the rest of your life.
> I agree with you but Ozempic is a bad example here. Part of the reason it is so valuable is that patients usually must take it for the rest of their lives. Its actually the perfect example of “evil” pharma since patients slmost akways regain the weight if they stop taking it. This leads to dependence or people searching for grey market sources.
Not really. Note that it's not taking ozempic for life vs taking nothing for life, but actually taking ozempic for life vs taking ozempic and 5 different medications for life when obesity related illnesses bite you in the ass. So generally ozempic still is "good" pharma (and the plot twist is that almost every pharma is good pharma!).
It's ridiculous to say that pharma is "evil" simply because it isn't a one time treatment, especially when you don't know if a one time treatment is even biologically possible. The water company isn't evil for failing to provide me a single glass of water that meets my lifetime hydration requirements.
> Part of the reason it is so valuable is that patients usually must take it for the rest of their lives.
Well yes, Ozempic doesn't solve the habits of a bad diet.
The weight rebound is surely due in little part to removal of hunger suppression as in "hormone rebound", but if you resume eating 5000+ kcal/day because you don't have something that keeps you from doing it, you'll end up in the same situation as before. Ozempic was never meant and is not going to fix your diet. That's a psychological and environmental problem.
Average person in the world earns about $300k in a lifetime. So it’s hard to charge more than that per person.
Which illnesses have been cured? Diabetes, cancer?
> From the human perspective, researchers are people, and they do have their incentives. Making a breakthrough, of any kind, is important for them - even if for their career (but many do genuinely care and want to help humanity as a whole).
Researchers are people, but they are paid and directed. They can't go off and do what they like. The corporation directs them, and they are paid for their efforts. Researchers (and all working people) aren't doing what is right - they are doing what they are paid to do.
All the financial upside for pharmaceuticals is in prolonged treatments. It is a 'long sickness' industry. This is perhaps too bitter a pill to swallow for most, so this is where marketing and education come in with the sugar.
I've hung out with a lot of pharma folks, and the business is really complicated. Most of the companies aim to both help people and to make a lot of money, and will choose projects based on some balance of those -- sometimes in dubiously ethical ways (e.g. tweaking formulations of existing products to extend the patent) and sometimes in basically fine ways (e.g. lots of the improvements in diabetes management which have helped a ton of people; at least the targeting is fine here though often not the pricing). Obviously chronic diseases that affect lots of rich people are a prime target to make money, so drug companies make lots of drugs for these, and they usually aren't curative because chronic diseases are hard to cure (but see e.g. Hep C which is now curable). There are also companies with rich investors who want to cure death, or at least cure particular diseases that they fear or have a genetic predisposition to (lots of unethical behavior from a certain now-defunct company that tried to do this).
For cancer in particular, pharmas don't (and mostly can't) just target a drug to chronically treat some cancer over the long term but not cure it. Instead they pick some target that's believed to contribute to development (/ metastasis / treatment resistance / whatever) in whatever cancer, and make a drug to interfere with it or to target an immune response to cells that make it. If it's stable, nontoxic, and looks potentially effective enough they'll take it to clinical trials. During clinical trials they'll find out whether it does nothing, gives you a few extra months, or has a chance at curing the disease. Usually the answer is that it does nothing or almost nothing, or isn't worth the side effects, and then the company wasted its time and money. Drugs with a chance to cure common types of cancer can be enormous successes -- see eg Herceptin.
Cancers are difficult diseases and it's rare to find something that reliably cures them. But drug companies aren't pulling their punches. Like they would never say "oh this drug clears breast cancer too reliably, we should make it less effective so that people will be more likely to die but also might take it for longer".
But researchers are not necessarily paid by corporations, and governments, foundations, and such are generally more willing to hand out grants that forego short-term profitability for long-term gains. And while a company might not be interested investing in research that could undermine one of their core products, that obviously does not apply to competing companies that do not already have corresponding products. What better way to break into a market, than to render your competitors' products obsolete?
> Which illnesses have been cured? Diabetes, cancer?
Chicken pox, polio, hepatitis C, dracunculiasis, yaws, malaria (on the way of it), tuberculosis, syphilis, everything that can be killed with antibiotics, rubella...
Remember a year or two ago when it was thought that measles was cured in the USofA?
Halcyon days.
There is a cure though. What is happening is just that people are too stupid to use it.
agit-prop works, and the rube demographic is only growing larger because of it
see also: right wing grift
Imagine your role is allocating spending on $10B/year of medical research and you are presented with two strategies: spend everything searching for the cure for one poorly understood condition, or allocate to treatments improving standard of care for 100 conditions.
Improving standard of care for 100 is less risky/more profitable because you have more shots at an expensive process with a high failure rate. And it is a lower bar to improve patient care than to permanently fix a medical mystery. But there is another factor. Focusing on treatment/management over cure most likely maximizes the positive impact on patients within the the constraints you work under.
There have been at least three new major treatments for a chronic thing I have that received FDA approval over my lifetime. Those treatments have had a massive impact on my quality of life, ability to have a career, etc. I don't believe that happens for me if we allocate to cures.
I'm genuinely glad you have new treatments and its improving your quality of life.
The point I am making is that you are a/ not getting cured, and b/ paying a lot of money. The reason for this, is this is best strategy for maximising profits. Its really the exact same model as your local heroin/crack dealer.
Please set me straight if those conditions differ in your case.
Profits are what pharma companies want.
The consumer is mostly labouring under the illusion that companies want the best for you. They are not your mum. They want what's best for them. And, most people would do the same - no one is gifting anyone health.
All I'm saying is let's drop the illusions and fantasy and call a spade a spade.
The local illicit drug dealer comparison doesn't apply because you can't simply ignore the development time and cost of FDA approved drugs. My post was about allocating limited capital to pharmaceutical research, and maximizing benefit.
Again, if your choice is improving quality of care for 100 conditions or trying to moonshot your way to curing one disease, more patients benefit from the former even if pharma also profits more.
> Which illnesses have been cured? Diabetes, cancer?
Type I diabetes - no, but this is a condition in which the body attacks the part of itself that makes insulin. So by the time it happens, it's too late. Sadly, we're generally bad at understanding and preventing autoimmune diseases, but this needs more basic research, not drugs.
Type II diabetes - essentially a lifestyle condition. May be functionally cured in some/many cases with strict lifestyle interventions. Ironically, GLP-1s may help move some people towards a functional cure.
Cancer - yes, where possible. The open secret is that the best way to fight cancer is to not get it in the first place, or failing that to catch it very early, but these are issues of lifestyle and public health policy - both of which we're currently very bad at optimising, as a species.
> All the financial upside for pharmaceuticals is in prolonged treatments.
Except for the examples to the contrary.
Even without understanding pharmaceutical research, your claim to understanding business strategy is braindead: there is not 1 pharmaceutical company. And many pharmaceutical companies work on treatments for the same conditions and diseases.
Why would any competitor sit on a cure for a condition there opponents can only treat when in the short term you'd post amazing next quarter profits, and in the long term you'd financially diminish that competitor in the market place even if we grant the position that you are somehow able to find treatments that aren't cures (others have explained ably why this isn't how it works).
Everything looks like a conspiracy when you don't understand anything.
Plus even if it does involve expensive drugs and long term treatment, that would be a huge step towards cheap drugs and short term treatment.
Lots of treatments start expensive and then come down in cost as competitors step in.
Patents run out also.
They want something that actually works, foremost. If the thing they sell doesn't work, then when someone figures out something that does work the thing that works will be preferred by the doctors.
to put a finer point on it, to be able to gouge sick and slowly-going-crazy people for lots of money you have to have something that actually solves the problem.
can't mark-up snake oil, not in ways to shift the stock price for Fortune 100 tier companies -- too many lawsuits and visibility
https://www.statnews.com/2019/06/25/alzheimers-cabal-thwarte...
"Despite being described as a “cabal,” the amyloid camp was neither organized nor nefarious. Those who championed the amyloid hypothesis truly believed it, and thought that focusing money and attention on it rather than competing ideas was the surest way to an effective drug.
It has not worked out that way. Research focused on amyloid, and the development and testing of experimental drugs targeting it, have sucked up billions of dollars in government, foundation, and pharma funding with nothing to show for it. While targeting amyloid may or may not be necessary to treat Alzheimer’s, it is not sufficient, and the additional steps almost certainly include those that were ignored, even censored. Probably the most shattering turn came in March, when Biogen halted the study of what proponents called the most promising Alzheimer’s drug in years — an amyloid-targeting antibody."
I still refer to this article seven years later. Groupthink in the medical research space sets back progress by decades. And it's not just Alzheimers. The FDA's approval process is stymied by a CYA culture that fails to adopt the risk profile it needs to in order to potentially save large contingents of sick and dying.
> The FDA's approval process is stymied by a CYA culture that fails to adopt the risk profile it needs to in order to potentially save large contingents of sick and dying.
Except the history of FDA approval here is that it has been too accepting of drug candidates for Alzheimers with very weak evidence of efficacy and serious side effects. This particular field would probably be better off if the FDA took a harder position on efficacy, rather than deferring to drug companies and patient/caregiver groups that desperately want something.
I would like to see the FDA get rid of their binary "Approved" approach.
Instead, at the start of a treatment on a patient, an analysis must be done of all available data, and the treatment only allowed if the error bars put it within the realm of the best treatment available.
That means at the start when not much data is available, it is easy to give it to a patient. But over time as more data comes in it gets harder and harder to do so if the treatment is ineffective or harmful.
Data should be collected and analyzed in real-time - it should be a matter of hours between some life event like a death feeding into the dataset used for decisions on new patients.
The struggle is the high level regulatory bodies (with the exception of aberrations such as the current admin's approach to appointment) generally select for individuals with a low risk tolerance. Low risk tolerance is generally incompatible with speed - it's a miracle the covid vax and treatments were approved as quickly as they were in 2020.
Biggest example of this risk aversion is the peptide craze going on (the most famous of which are GLP-1 antagonists). It's pretty much a wild west where people read a low-sample animal study, and buy a drug that's "for research only, not for human consumption" off of a compounding pharmacy in China.
Few human studies because even if you have willing and enthusiastic volunteers it's too expensive and creates legal liability. And the FDA cannot approve it without a high bar of evidence (for effective treatment and low risk) and costly, time consuming reviews. Because of this, there is a black market for the things and people are basically being their own test subjects.
> The struggle is the high level regulatory bodies (with the exception of aberrations such as the current admin's approach to appointment) generally select for individuals with a low risk tolerance.
This may be true, but I don't think it's the major driver of conservatism. Two thoughts/observations:
1) Bodies like the FDA face a strongly skewed set of incentives. If they take a risk on something and people get hurt, they face huge public criticism. If they take a risk on something and it's all fine, very few people care or notice. As such, they are strongly driven to not make a public mistake - which drives ever more conservatism.
2) FDA can actually be innovative compared to other health authorities. Breakthrough therapy designation, Project Optimus, Project Frontrunner, and others - show this. However, they've got a strong 'not invented here' mindset - they flatly refuse well-meaning individual innovations from pharma companies, if they're not compatible with FDA's guidelines. And they're heavily bureaucratic, meaning the innovations that do appear are usually following years of process (which probably links back to #1).
This does happen. SAEs are reported in real time, and they do halt trials sometimes. Also, there is often a condition of approval that requires ongoing data collection for adverse events post-approval.
I was outraged when I first read that article, but taking a step back and catching up on recent progress, I came to the same conclusion you did. Words like "nefarious", "fraud", and "corrupt" were thrown around, but no one was actively was seeking to do harm.
The harm was done by the groupthink and the sucking up of resources to research alternative causes. One of the comments on HN when that statnews article was first linked was by a commenter who worked on Alzheimer's. They agreed and I remember the line, (something to the effect of) "if you wanted funding for alternative investigations, you had to still throw a bone to beta amyloid in your proposal."
Was it all a waste? No. Current thought is beta amyloid is still involved, but Alzheimer's is multicausal. What those other causes are is in its investigation infancy. We could have started investigating those decades ago if the scientific research complex were truly open to new ideas.
This is similar to what we see in software architecture. There's a team that picks a framework or pattern early, then builds everything on top of it, and by the time evidence shows up that the foundation was wrong. Now, switching costs are so high that it's cheaper to keep building on the broken foundation than to start over. The amyloid hypothesis reminds me of technical debt. The "cabal" wasn't conspiring, but they were just rationally protecting their sunk costs, same as any engineering org that can't migrate off a bad database choice.
There's a lot of this going on in science. Once the common accepted truth is "X" papers that are counter to X or show that X is not true, end up not getting published and then funding dries up.
The scary part is that everyone can be acting in good faith and still produce a monoculture
They say science advance one death at a time.. let's hope LLM/AI can fix that by giving resource previously inaccessible to smaller players to be able to show results against the consensus.
Otherwise we just need to hope that we live long enough and don't catch ALZ until the current ruling peer group pass.
The major problem has been lock-in of the Abeta 42 peptide fragment as the cause. This monomaniacal focus was rewarded by grant awards to team players.
Karl Herrup has a terrific book on the topic How Not to Study a Disease — The Story of Alzheimer’s from MIT Press (2021, ISBN 9780262045902). He did not win many friends but I think he is right.
The consensus now is that many factors contribute to the heterogeneous diseases we now call Alzheimer’s.
The article (or I guess more accurately "podcast transcription") seems to be saying that this lock-in essentially happened due to fraud, since some of the data was intentionally doctored to get the intended result. One of the guests seems to be an author of a different book about this (with the other guest being the scientist who apparently uncovered this). I can't personally attest to the accuracy of anything they said, but they're at least alleging that it was a lot less benign than it sounds like you're describing.
The focus is definitely on scientific fraud, but what makes the fraud so easy in this case is singing and selling the same song that the big teams are singing and selling. You can fly under the radar AND get funded, and if you are “lucky” become an ultra big shot like Masliah at NIA.
I don't buy the fraud explanation as the full explanation. Other areas of medicine (stem cell) has had bigger incidents of fraud on top of other major headwinds, and still has made more progress.
Fraud is everywhere and we still move forward in most arenas.
In ALZ and the plaque cartel the fraud was foundational and the overwhelming source of funding for research was tied to supporting that hypothesis. The big issue, even if you have a competing theory, is that the diagnostic criteria relies heavily on the plaque and presence of indicators. So you get a group of people who have elevated plaque and MCI, but many people have elevated plaque without MCI, and just as many people have MCI without elevated plaque.
So if your cure is targeting something different but the group of people you have are selected from this cohort of maybe afflicted people then it's really hard to get a significant result. Plus you tend to be dealing with old people, that have other health issues that MCI isn't causing to get any better.
The stem cell field is also quirky. IMO it is one of the most cutthroat, competitive, ruthless fields of life sciences that is new enough in history to still have a bunch of pioneers fighting to be the figurative Oppenheimer. One PI’s fraud is quickly detected and fought over.
Meanwhile the Alz and Neuro field as a whole are well established, and the amyloid hypothesis was a foundational theory taken as a fact. Any initial questioning of this and they would brand you as a lunatic.
Reminds me of schizophrenia. A hodgepodge of different things lumped into a single label of "broad class of things we don't understand"
Some day autisim, neurodivergent and ADHD can join that illustrious list.
There’s another book mentioned in the podcast called “Doctored.” The gist is: bogus “science” led to loads of money / research going in a direction that was effectively fiction.
People love to praise “the science” when they mean the scientific method. What they always seem to forget is that method is executed by humans. Imperfect, sometimes ego driven humans.
The genetic evidence that amyloid-beta is in some way causative of at least a subset of Alzheimer's disease is still extremely strong.
The fact that amyloid-beta binding drugs like Lecanemab and Donanemab decrease progression is also very strong evidence for the amyloid-beta hypothesis.
What seemed to be the hurdle was likely, that targeting amyloid-beta in its pathological form just wasn't easy and developers of pharmaceuticals instead focused (for unknown reasons) on the solid amyloid-beta grains in the brain.
The major reason things are moving so slowly is because of the long development times of pharmaceutical compounds. A new compound will at least have to spend 2-3 years in safety studies before being tested on its first real patient, and then for Alzheimer's, which is a slowly developing disorder, nothing short of a 2-year followup time will show efficacy unless it's truly a miracle compound.
Unfortunately the evidence that targeting amyloid (e.g. Lecanemab and Donanemab) improves the symptoms of Alzheimer's disease is very weak. See the latest systematic review [0]. This does not mean however that amyloid plays no role in the disease, the treatment may simply be too late.
[0] https://www.cochrane.org/evidence/CD016297_are-medicines-ant...
That systematic review is unfortunately severely flawed. They pooled the old anti-amyloid antibodies (which everybody agrees are inefficacious) and were never used outside clinical trials, with the new anti-amyloid antibodies, that does show modest efficacy in reducing the speed of progression.
While these two classes of drugs target the same molecule, they are developed to target amyloid-beta in very different forms. Pooling all those drugs together, and then showing very weak effect, makes absolutely zero sense, and I hope and expect this review to be pulled soon.
The point of systematic reviews is to be un-biased. So if their question is whether targeting Aβ amyloid is a valid approach they have to include the unsuccessful trails as well as those purported to be successful.
As to the trials specifically for Lecanemab and Donanemab, the benefits are not claimed to be either strong or large, even by those who support it. The current support these receive is more aligned with the concept that an improved targeting of Aβ amyloid might improve outcomes. This remains to be demonstrated.
I don’t quite follow the reasoning behind this being “unbiased”. Studies must be designed to answer specific research question. What is the question being asked by the study in question. If the question being asked is whether AB the right target (in humans), then it would need to consider other forms of human evidence, such as genetic evidence, alongside alternative explanations of failure — bad molecule, wrong isoform, bad cohort selection, etc.
The question asked in the Cochrane review linked to above is whether there is evidence that current treatments targeting amyloid provide relief. Their conclusion is that the effect is too small to be considered beneficial. Especially when considering the undoubted side-effects, which include edema and micro-bleeding in the brain.
It doesn't ask whether amyloid is causative of the disease.
I wonder. Because if that was the question, why would they include anti-amyloid treatments that were never approved and are not part of any current treatment regimen and dilute the real effect of the approved antibodies? (Not that the approved antibodies are a silver bullet, but clearly they have some positive effect.)
The Cochrane review did not ask the question of whether Lecanemab (for example) worked, it asked the more general question of whether targeting amyloid worked. If targeting amyloid, generally, worked you might expect all approaches to targeting amyloid to show some efficacy. So they included all those for which clinical trials had been conducted. Obviously some treatments didn't pass the threshold required and so were not subsequently approved. If you only included successful trials you would bias the outcome.
It's possible, of course, that some methods of targeting amyloid might work where others failed. But even those that claim success (Donanemab and Lecanemab) have a very modest benefit.
Yes, the new anti-amyloids are not a revolutionary therapy. But they do have a small but definite effect on disease-progression. (something which in a highly noisy indication like Alzheimer's may actually mean a lot more to the patients than it seems by looking at the data. E.g. donepezil and memantine have very modest effects too, but patients and caregivers are still surprisingly positive about them).
And since these were developed using different methods and epitopes, it does not make sense to pool them together when doing a comparison. It's obvious that if you combine modestly beneficial compounds and compounds with zero beneficial effect then the mean effect will be worse than the modestly beneficial compounds.
And when you do so just because they were aimed at the same molecular target, not even considering if anyone claims that the old, unapproved antibody-therapies, with no positive studies to support them, have any effect, what you are doing is somewhere between extreme ignorance and deception.
All the trials included in the Cochrane review demonstrated removal of Aβ amyloid from the brain. Side effects were relatively modest, except for edema and micro-bleeds. So they are all legitimate tests of the hypothesis that removing Aβ amyloid would be beneficial.
No you would not expect all efforts to target AB to work. You can have the right target and the wrong molecule. Look at GLP1s as an example. Multiple pharma companies tried GLP1 receptor agonists for more than a decade and it was not until recently that Novo and Lilly got them to work.
The first GLP-1 receptor agonist to enter clinical trials was exenatide by Amylin Pharmaceuticals. It worked from the get go.
But has only weak/moderate effect on weight loss compared to semaglutide, tirzepatide and retatrutide.
Alzheimer is a lot more difficult to measure than weight and amyloid-beta in the brain obviously significantly harder to target than the GLP-1 receptor in the body.
Also, a review pooling together all GLP-1's (including those that failed in development) and concluding that they as a class have only moderate or weak effect on weight loss, would obviously be badly misleading.
If you grouped all GLP-1 agonists that had entered clinical trials, they would be shown as successful [0]. No GLP-1 receptor agonist has failed to reduce appetite in clinical trials, but some were better than others.
The point about the anti-amyloid trials is that they all succeeded in removing amyloid. But they did not improve cognition, and only some resulted in a slightly slower rate of decline in cognition (people still declined).
[0] https://pubmed.ncbi.nlm.nih.gov/39841962/
>Forty-seven RCTs were included, with a combined cohort of 23,244 patients. GLP-1 RAs demonstrated a mean weight reduction of -4.57 kg (95% CI -5.35 to -3.78), mean BMI reduction of -2.07 kg/m2 (95% CI -2.53 to -1.62), and mean waist circumference reduction of -4.55 cm (95% CI -5.72 to -3.38) compared with placebo.
This is ridiculous.
Your meta review has like 80%-90% of the studies on semaglutide and liraglutide. When finding random effect per drug, they even say this:
> Hence, the drugs eligible for meta-regression were semaglutide (subcutaneous injection, once weekly) and liraglutide (subcutaneous injection, once daily), which both showed a dose-dependent treatment effect in terms of weight and BMI.
And the class-effect is much more modest than semaglutide by itself would have shown, exactly as I said. What is the point?
Both meta-analyses above cover all eligible clinical trials for the respective strategies, targeting the GLP-1 receptor, or targeting amyloid.
For the GLP-1 strategy, Table 1 in the above paper shows that all drugs were clearly effective. Some were better than others.
For the amyloid strategy, only some of the drugs were effective, and that efficacy was very weak, even when all the drugs removed amyloid. This brings into question the hypothesis that removing amyloid would alleviate AD, i.e. the slender benefits of Lecanemab might not be caused by amyloid removal. The same cannot be said for the GLP-1 receptor agonists.
Agreed, especially in some subpopulations. I think the strong case today is to research it's use in people with Dawn's syndrome (accelerated development Alzheimer's Disease due to 3 copies of the APP gene). Target it only to people with those 3 copies.
It's legimate as people with DS have a hugely increased risk of AD. Their risk increase seems likely related specifically to Amyloid. Many with DS can consent to it.
In general my completely gut feeling is that once we can target Tau we might find that targeting amyloid is needed to fully curtail progression.
Agreed, using these anti-amyloid treatments at an early stage in people with a high risk of early onset Alzheimer's disease, such as those with Down's syndrome, is likely the most robust test available of the theory that Aβ amyloid is directly causative of this disease.
Trials are currently ongoing. The results should start trickling out in a few years...
I'm surprised there was no mention (at least none that I found when searching) of the relatively recent research coming out of Harvard regarding the hypothesis that low levels of lithium in the brain are responsible for a lot of Alzheimer's cases.
The research is still in the very early stages (largely mouse models, though they did develop the hypothesis by looking at differences in human brain tissue post mortem), but to me my biggest fear is that little research will be done because the "cure" is a commonly available, non-patentable supplement, lithium orotate.
As someone in middle age with a family history of dementia, I've decided to start taking lithium orotate because the risk/reward profile looks so good from my perspective. Lithium orotate has been sold as a supplement for decades, and at those levels it is very safe with extremely-small-to-no chance of adverse effects (e.g. https://www.sciencedirect.com/science/article/pii/S027323002...), so I figure the worst that can happen is I'm wasting my money, but I'd take that for even the small chance that it helps ward off dementia.
Nah, lithium is only treating something that is occurring much deeper: low glucose transport in the brain.
https://pmc.ncbi.nlm.nih.gov/articles/PMC8772148/
This is why APoE e4 alleles are a risk factor, because they control glucose transport.
https://www.nature.com/articles/s41398-025-03550-w
The brain is just losing energy.
Interesting. I'm also taking orotate, and like the other comment here, it makes me very sleepy (so I'm taking much less than 1mg/day). Maybe that's the brain working to "take out the trash?"
Earlier today I read a comment here mentioning Dr Michael Nehls who writes about lithium and also dementia (highly recommend his books). Now that comment is no longer there. Hmmm.
I agree with your post and the well-studied safety of it in humans at appropriate doses :) but the study you linked is on rats; and so there’s probably another better study to link.
I experiment and take a small number of less-commonly-known supplements and those kind of studies _in itself_ should never contribute to “it’s safe for humans”.
Anecdata: my personal brain/body didn’t react too well to 1mg a day, I felt somewhat ‘sluggish’ and found concentrating harder, so I stopped after 2 days out of being conservative. Perhaps I’d get used to it, but for me personally, I was surprised at the effects of just 1mg so I didn’t want to continue taking it.
To add some context on the study I linked - that particular study was only focused on understanding why, after decades of use by humans as a supplement, that lithium orotate has so rarely been reported in any cases of adverse effects (all the cases I could find were acute toxicity from taking way too much, like the 18 year old woman who took 18 capsules at once, and still only suffered nausea and some mild tremors). So that study found none of the effects on specific organ systems in rats that you often find in other substances that have higher rates of adverse effects.
My point being, if that was the only safety study done on a brand new substance, I'd agree with you, but the safety profile really boils down to the decades of human use as a supplement.
All that said, I totally agree that many more human studies are needed to determine the actual efficacy of lithium orotate in preventing or reversing dementia.
It’s actually quite simple: 1–5 mg lithium orotate, vitamin D, omega-3 from algae with high levels of polyphenols, a daily exercise routine, and good food—not the processed crap you often get in the US. My grandmother is 94 and still mentally so sharp that she amazes me every time.
https://michael-nehls.de/
It's actually not "quite simple" at all, and I think there is a gulf of difference (often misunderstood) about taking supplements as a personal decision because there is low risk of harm, there is some preliminary evidence they may be helpful, and one can afford them, versus touting them with certainty as the cure to a whole host of ailments without sufficient evidence, which is usually what "wellness influencers" and people selling supplements and "health optimization" programs do.
My grandmother lived to 102 and was mentally sharp right up until she died. She also smoked daily into her 90s.
Was she diagnosed with Alzheimers, which she then managed to halt the progress of?
Every time I read about it and get jazzed I take it and feel awful. I’m guessing my brain chemistry is better without it.
Any side effect goes away if you reduce the dosage sufficiently. In the recent Harvard study the dose was very small when you convert it to a human equivalent dose.
So does any effect as well, though.
I do try small doses.
Apparently not small enough ("feel awful")
Awful how?
My spreadsheet says it makes me feel incredibly sleepy.
I took lithium for <redacted tendancy> it got to my kidneys never thought of more generally microdosing lithium. Interesting. Full dose yeah flat and sleepy. Not sure it was the reason for flat out brain rot. (Other factors were available maybe just getting older.) Full dose needs blood tests as overdose weirdly bad. From <relative> due to dehydration / holiday in the sun looked like almost drunk but not drinking slopy etc. Slightly clingy desparate for interaction with strangers. <Other factors could have been available>. Not informed of damage relative seemed to recover ok. <Nationalised medical system>.
Ok got minus 2 for that gotta rant elsewhere.
"Do not attribute to malice what can be attributed to incompetence" and all of that, but...
Alzheimer's (like a gazillion other diseases) is a product of senescence, and senescence is a subject that faces strong ideological headwinds. That leaves the medical system in a situation where they want to treat the symptoms (the diseases) instead of the root cause, and treating the set of symptoms that we call Alzheimer's is going to be tough.
The single best predictor of Alzheimer’s disease is chronological age. Yet of NIA’s $4.5B FY2025 budget, about 60% goes to Alzheimer’s and related dementias; only 9% to the Division of Aging Biology, which funds the basic mechanisms of aging itself.
The insider joke is that the “A” in NIA stands for Alzheimer’s. The deeper and sadder joke: when you fit cognitive trajectories within the subset of people who go on to develop AD, about half of the variance in their test scores is accounted for by chronological age alone.
We’re spending seven times more on the disease than on the clock — and the disease is mostly the aging clock.
Go figure.
As a society we are so used to seeing our grandparents and parents die that thinking otherwise is near impossible. I wish we saw ageing as a disease it is, instead of a "natural therefore good" thing.
Yes, and less than $1 billion/year spent on the basic biology of aging by NIH/NIA. Funding for research on the root causes of aging is decimal dust compared to distal consequences such as cancers, cardiopulmonary diseases, renal failure, immune diseases, Alzheimer’s, etc.
NIH is great at tactical research but terrible at strategic research, and politicians do not help much ;-)
The brain is a dynamic system, and a poorly understood one at that. It relies on active processes in order to not degenerate (likely the main reason why sleep deprivation is eventually fatal). Science is still some way from cataloguing all the processes involved, never mind fully understanding their workings.
Alzheimer's isn't a single-point-of-failure disease, more like a dysregulation of maintenance. So there are lots of things that can tip the odds one way or another, and we may get a lot better at prevention - to the point of reducing incidence maybe five-fold, or delaying its symptomatic onset to beyond the relevant lifespan - but the idea that there might be a single "cure" seems like wishful thinking.
It may also prove to be that, like a spinning-top, once things start to go off-axis it may be very difficult to restore the original stable state, and at most we can just slow it down a bit.
Perhaps more uncomfortable, if most of the effective interventions, risk-reduction-wise, are social/lifestyle related, that has implications for whether people have the agency to access those things.
(Time/energy/facilities/resources for exercise/active lifestyle being an obvious case in point, which is already well known to have a moderate protective effect).
Unable to read the full article, however the amyloid hypothesis is not without solid scientific foundations.
Alzheimer's disease may occur either due to inherited mutations in the genes for APP or presenilin, in which case it can occur as young as 40 yrs old. Or it may occur "sporadically" in those over 65yrs old. The brain pathology of both is similar. Notably, amyloid is derived from APP in part by the action of presenilin, which cuts the APP protein to release the amyloid peptide (Aβ).
Currently, the amyloid hypothesis is the only known way to reconcile the similarity of pathology (for both amyloid and tau) between early onset inherited AD caused by mutations in either APP or presenilin, and later onset sporadic disease. Furthermore, all the mutations in APP that cause Alzheimer's disease are located within or adjacent to the region that corresponds to Aβ amyloid, and not in the remaining 95% of the molecule.
Until another way of unifying these observations is found, the amyloid hypothesis will always find supporters.
I did undergrad research on amyloid aggregates in 2010, with Alzheimer's as the motivation. I remember papers coming out then making it pretty clear that there was no real mechanistic link between them. It was basically just a symptom. That was 16 years ago.
'Science progresses one funeral at a time...' It is often the case that an entire field is led by a few influential people and until they leave others can't get the air they need to make real progress.
And this can happen even when everyone involved is smart and sincere
I think you're right. Anyone brave enough to suggest areas of investigation where there is evidence this has happened?
I'd argue the reason we’ve spun our wheels on Alzheimer's for decades isn't just about a flawed amyloid model. It’s a symptom of a much larger, dying paradigm in biotech.
For decades, the industry standard was to hunt for targeted small molecules to solve singular biological issues. And to be fair, I don't think this was because of a lack of vision as it was simply the strict limit of our technological capabilities at the time. But attempting to treat a cascading, systemic disease like Alzheimer's with a single targeted molecule is like hoping replacing one pipe will solve the problem when the issue is that the entire plumbing system is corroding.
This fundamental mismatch is exactly why clinical progress has stalled, and I believe the future of treating Alzheimer's will instead closely mirror how our approach to oncology has evolved.
We spent years searching for a universal molecule to cure cancer before we accepted reality. We now know that effective treatment often requires sequencing a tumor's mutanome to develop a highly personalized intervention for the individual. As neurodegenerative systems fail with age, we face that exact same biological complexity. A traditional small molecule is not going to rescue a globally failing network.
My personal take is that we won't see a true breakthrough in Alzheimer's until capital fully rotates out of these legacy, single-target pipelines and into programmable biological systems.
TLDR: gatekeepers stifled exploration and innovation.
When a topic only has a limited number of experts, those experts become gatekeepers.
Those gatekeepers directly or indirectly control research funding.
Gatekeepers necessarily harbor biases, some right and some wrong, about how the field should progress.
For Alzheimer's, some gatekeepers were conflicted and potentially directed the field in the wrong direction. Only time will reveal AB42's true role.
It's easy to find fault in Alzheimer's.
It's harder to see the general solution to the gatekeeper problem, i.e., how to allocate resources in areas with limited experts.
> gatekeepers directly or indirectly control research funding.
Perhaps funding like public grants could be controlled by few? Should not the case for private money?
Relatively common health issues older people tend to get fair amount of private funding after all.
Rich people tend to be older and they are lot more likely to see amongst their friends and family Alzheimer's and Parkison's or even cancer and so forth and be worried about it and thus donate money to them.
In somewhat related (i.e. old people health concerns) life extension research gets all kinds of wacky non traditional research lines get funded all the time, I don't understand why would Alzheimer's would be any different.
If you're a wealthy person lacking a neurobiology background, how do you decide which research efforts are the most promising? Which labs do you back?
Generally, you rely on experts.
Who typically became experts by adhering to the conventional wisdom set by gatekeepers.
"Science advances one funeral at a time" feels apt.
Sadly, the problem isn't confined to Alzheimer's.
Whenever only a few people decide what is "right," the same pattern of stifled innovation will generally manifest itself not by design or from malice, but because it's hard for a small group to be 100% right on what works and what doesn't -- especially on matters as inscrutable as neuroimmune diseases.
I don't think the problem is nearly as big as people claim. Experts are often right!
While there are counter examples and inefficiencies in the system (and there are idea of addressing this, by distributing some part of the money in other ways), we have far bigger societal issues because people do not believe in science, especially where there is an industry lobby sowing doubts.
So I really want to push back against the the idea that the scientific system is broken. While there are real issues, this is still very misleading.
What also happens is these gatekeepers end up being those requested to review papers. When a paper comes up for review that challenges the status quo these gatekeepers nit-pick the paper and recommend it not be published. This happened to my wife on numerous occasions. She has a few unpublished papers because of this. What she found in her research has since become the common accepted knowledge in her field after a few funerals.
Life extension seems like the kind of thing that can get private funding with relative ease specifically because they aren't trying to compete with the government. There are a lot of private foundations that give out grants too though.
Life extension in the private sector is dominated by hocus-pocus and unwarranted optimism. The genetics of mortality is amazingly complex. See this open access monster paper that came out in Nature this week—admittedly “in mice” on mortality and genetic of longevity.
https://www.nature.com/articles/s41586-026-10407-9
(I’m an author)
In most engineering fields we don't give the monopoly to people until they have actually demonstrated success beyond a reasonable doubt. There will always be groups of people claiming that the math/methods they happen to know are the best at explaining some behavior (even now there is that learning mechanics paper on top page)
The takeaway is to stop pretending that we can do good science when the ambiguity is so high, the majority of funding should go to people working on more concrete problems. We never locked in on vacuum tubes because the downsides were so obvious and the upsides of silicon transistors (if they could be made to work) were also obvious even to people outside the field, where your talent comes from. At the very least funders can't allow shifting goalposts, make them up front answer questions about the drugs. That will give you something to estimate the value of the drug and then when they come back with study after study outside the ranges they gave, you lower their funding. E.g. This is supposed to work on someone who was stage 2 and stop progression and then 5 years later it only "works" for stage 1 patients.
Strange breakthrough ideas can't even exist in the current system structurally, so going this route is the only logical choice. Which begs the question, why aren't clinical trials a private venture already? Governments are burning billions of taxpayer dollars for either nothing or cynically to keep the boomers alive and voting even longer, while 1/5 children are obese. For the rest of us we've socialized the risk and privatized the profits.
[dead]
It's because there is little progress in uncovering the mechanisms of the disease. Alzheimer's et al are tau-opathies and Parkinson's et al are synuclein-opathies. Both are degenerative and we wait for their common base in a Grand Unified Theory.
I like to view degeneration of any tissue as death due to (premature) aging. So, if we treat it, we achieve immortality by applying it to all body. This is something hard.
Grand Unified Theory:
Low intracellular ATP/GTP.
https://www.science.org/doi/10.1126/sciadv.adq6077
The "premature aging" framing makes sense, but I wonder if it risks hiding the disease-specific parts
There has been massive progress in neurodegeneration research. We now understand that the brain has a complex system for processing metabolic "trash." Like all systems it has a number of components, each of which can fail. This is why a single "silver bullet" drug will likely never exist. A multi variable systems failure can not be fixed with a single variable solution.
Alzheimer’s occurs when Amyloid/Tau debris accumulates faster than the glymphatic system can export it.
Parkinson’s occurs when α-synuclein (Lewy Bodies) accumulates because the cellular recycling system (Mitophagy) has failed.
While Choline is a critical bottleneck for Alzheimer's, Glutathione and GBA enzyme activity are the primary bottlenecks for Parkinson’s. But in both cases it depends on the person and their genetics and what matters the most. If someone is at high risk for Alzheimer's a multi-pronged approach will probably be very common. For example a post menopause woman who is not on HRT, but at high risk due to parents should be getting Choline due to the low PEMT expression, but they might have a higher risk for neuroinflammation via NLRP3 and so need to also combat that too.
To say no progress has been made is to ignore the fact that we have learned a ton about the various components of these systems and how they can break down.
Here are the two approximate decay equations that you can put into an online latex viewer.
Alzheimer's
\Psi_{AD} = \int_{0}^{t} \frac{[(\mathbf{K}_{\tau} \otimes \mathbf{K}_{A\beta}) \cdot \mathcal{I}_{NLR P 3}]}{[\mathcal{G}(Li \cdot GSK3\beta^{-1}) \cdot PRO(ER\alpha \cdot \text{PEMT}) ] \cdot \Omega_{ATP}} \cdot e^{\left( \frac{\Gamma_{\text{fibrosis}} \cdot \text{PAI-1}}{EPA \cdot \text{Natto}} \right)} \, dt
Parkinson's
\Psi_{PD} = \int_{0}^{t} \frac{[(\mathbf{K}_{\alpha\text{-syn}} \otimes \mathcal{I}_{LRRK2}) \cdot \mathcal{I}_{NLRP3}]}{[\mathcal{G}(\text{Parkin} \cdot \text{PINK1}) \cdot PRO(\text{Dopamine}_{\text{flux}})] \cdot \Omega_{ATP}} \cdot e^{\left(\frac{\Gamma_{\text{Oxidative}} \cdot \text{Iron}}{\text{Glutathione} \cdot \text{GBA}}\right)} \, dt
And for good measure here is cancer
\Psi_{Onco} = \int_{0}^{t} \frac{[ (\mathbf{M}_{mut} \otimes \mathcal{G}_{growth}) \cdot \mathcal{I}_{STAT3} ]}{ [ \mathcal{G}(p53 \cdot \text{PTEN}) \cdot PRO(\text{Anoikis}) ] \cdot \Omega_{ATP}} \cdot e^{\left( \frac{\Gamma_{hypoxia} \cdot \text{VEGF}}{\text{Repair}_{DNA} \cdot \text{Immune}_{flux}} \right)} \, dt
The point of these isn't to give an exact equation, but to make the understanding of the systems and their components radically simpler for humans to understand which can help with treatment leading to questions like "Where is the bottleneck in this patients system?”
"One possibility: a leading hypothesis pursued by researchers (and funders) was built on science that now appears to be fraudulent."
Possibly the most likely possibility?
There are multiple factors, but the one that contributes the most is that it's actually a very challenging disease to study and improve on.
1. It acts on the brain, one of the organs we understand the least.
2. It's relatively slow acting, and easy to miss in the early stages.
3. It impacts the older population which will have confounding health factors.
4. It doesn't fit neatly into a big category we already know a lot about, like infection or cancer.
Elaborating a bit - brain is hard to study since you can't easily take a biopsy of it (from a living person at least), and various brain scans are not great at identifying the stuff we care about.
The slow acting nature of it means also you have to wait a long time to see results of clinical trials; also because early stages are easy to miss that also means you are stuck studying people who are already pretty senile and thus might be beyond the point where you can make a big difference.
Ruxandra has a nice piece, focused on cancer, but the reasoning is basically the same here: biology is just really hard. Sometimes we get lucky but in general it's a long, slow slog.
[1] https://www.writingruxandrabio.com/p/why-havent-biologists-c...
And as with a lot of cancers, it seems to be perturbation of a dynamic system rather than a single, mechanistic cause.
Think of it like brushfire in an ecosystem, or species population imbalances leading to catastrophic breakdown. These are better understood in terms of system state and preconditions, as opposed to a trigger event.
Infectious disease, at least in the classic acute form (whether that's bacterial and fast - cholera - or viral and slow - HIV), is a more mechanistic process which can be halted by blocking a single step in its pathway.
Systems that remain healthy and balanced via dynamic processes are harder to reason about and fix, because the root cause of a disease state can be dozens of little things adding up to the system losing its ability to maintain homeostasis.
You can't definitively diagnose it without an autopsy of the brain.
[dead]
I would people need to read the #1 post on HN today to get a clue why they are failing with Alzheimer's.
https://www.scientificamerican.com/article/amateur-armed-wit...
Just like that math problem, we are starting off with wrong thinking right from the beginning. Some researchers are already talking about this but the plaques are actually a protective response to a metabolic problem in the brain which has to do with glucose transport.
https://pmc.ncbi.nlm.nih.gov/articles/PMC8772148/
This is why people with dementia and Alzheimer's crave sweets so much:
https://helpdementia.com/why-dementia-patients-crave-sweets-...
Alzheimer's is not a neurological problem, it is a metabolic problem.
One of the most important ingredients of a proposal for a drug development program is viability: is there a path to market. The issue with Alzheimer’s is that until recently there was no practical diagnostic test. Without a test, there is no way to run a clinical trial. No clinical trial means no drug approval. Research is halted before it even begins.
The effects of Alzheimer’s are pretty obvious. I don't think not being able to detect it is much of an issue.
Cuba is making progress in this space. Good thing the US has been doing everything in its power to destroy the country
https://www.bellyofthebeastcuba.com/us-citizens-in-cuba-for-...
It's actually a major source of medical tourism towards Cuba
No it isn't. There's little evidence this drug works beyond some small studies done in Cuba by the people who developed the drug. The sum total of medical tourism to Cuba is quite small, no more than about 10k people per year. This is large due to their healthcare system lacking basic supplies like gauze and aspirin. Belly of the Beast isn't a real news outlet, its propaganda.
What is "a lot" of tourism is arbitrary but Cuba is obviously one of the most commonly talked about medical tourist destinations. Despite being strangled by the longest running US embargo (66 years) they managed to make a remarkable and free healthcare system. According to the World Bank and WHO they have the most doctors per capita of any country. Anyone that's worked in international crises is well aware of Cuba's army of doctors that they send to help out in disasters
> but Cuba is obviously one of the most commonly talked about medical tourist destinations.
No it isn't, and not by a long shot. The vast majority of medical tourists to Cuba are from the Caribbean, virtually no one else goes there for medical care. If you have money to travel for healthcare there are tons of better options, and most countries with national systems have VASTY superior facilities.
> Despite being strangled by the longest running US embargo
The US embargo which I don't support doesn't cover medical or agricultural goods. The Cubans received free oil and equipment from the USSR then Venezuela, and still couldn't manage to maintain any infrastructure. They can trade with any companies that aren't US based, and do. Their largest trade partners are Spain, and for agricultural goods the US. However the country is so badly managed and corrupt that they've turned all of that free oil, industrial equipment, and expertise into abject failure.
> remarkable and free healthcare system.
It's actually dog shit, and their own government admits that its plagued by shortages[1][2]. I personally have known several people who go there to perform free eye surgeries and have to bring their own equipment because the Cuban system doesn't have any.
> Anyone that's worked in international crises is well aware of Cuba's army of doctor
The UN has called this slave labor[3] on several occasions, and many people I've talked to who have worked with MSF and otehr international medical aid orgs all say the Cuban doctors are so poorly trained as to be dangerous to patients. The lack of materials in Cuba means they never get hands on experience with vital techniques.
Get out of here with this Hassan Piker bullshit.
[1] https://english.elpais.com/international/2025-12-14/we-are-d...
[2] https://cuba.miami.edu/business-economy/a-close-look-at-cuba...
[3]https://www.prisonersdefenders.org/2020/01/08/united-nations...
Surprised to see anyone mentioning this here, NeuralCIM has been talked about for years behind the iron curtain. They also developed their own COVID vaccine and send hundreds of thousands of doctors to countries in the global south but even rich nations when they need help dealing with natural disasters. The US is viciously targeting them doing incredible harm nobody ever talks about.
https://venezuelanalysis.com/news/us-hardens-sanctions-targe...
It's good to expose fraud and it does sound like this set back the field, but "Why has there been so little progress"? - probably because it's very hard? We barely understand how the brain stores memories.
I'm dealing with someone with this disease now and it's absolutely hell.
I'm surprised that better science never resulted from that lady who could smell it.
Joy Milne, for the uninitiated: https://www.npr.org/sections/health-shots/2020/03/23/8202745...
Which is about Parkinson's, not Alzheimer's, and did lead to some new science.
This is one of the craziest articles I've ever read. I feel like this should be a major ongoing news story...
Because of Joy, scientists developed a simple, non-invasive, three-minute skin swab test that analyzes sebum to diagnose Parkinson's. In laboratory settings, this test has shown an accuracy rate of over 90%.
Unfortunately that insight hasn't led closer to a cure.
It also turns out sort of bad to tell people they have a horrible neurodegenerative disease 10 years before the major symptoms start.
Why isn't everyone's mind blown? Well for the cynical explanation, look at the state of science education and what people said about Artemis, vaccines, etc. or optimistically, there are too many mind blowing discoveries to treat them all fairly.
This is what the replication crisis looks like in tangible effect. I feel that consensus around major questions should never form without totally independent confirmation of experimental results. Even if not due to intentional fraud, you have to worry about, systematic errors, p-hacking, or sheer statistics (a million experiments performed by researchers is likely to yield at least one 1-in-a-million statistical fluctuation that looks like a genuine result).
I'm not saying I'm the best informed on this topic, but I thought the root cause has been known for a long time now as degraded endocrine and cardiovascular function.
That's also why Alzheimer's can take so long to develop. It's just one aspect that we've chosen to focus on because it's more clearly noticeable, but it cannot easily be treated in isolation from everything else. If it was, it would regress quickly without fixing the root causes.
We truly do not know the root cause. There are plenty of folks with "degraded" endocrine, cardiovascular, and both systems. Most of them do not develop Alzheimer's.
How many of them have their lymphatic and glymphatic systems effectively halted by parking their bodies in a chair or being bedridden?
Even the most unwell person (in the US) is still dragging themselves to the store and work, on average.
Simple, brief movement that we often relieve the elderly of is the pump that actions the lymphatic system.
Being older brings its own additions to the table.
There is no single root cause. Many scientists have preferred to ignore this fact and that has been a serious problem. Everyone likes a simple story. Age-related diseases are not simple stories.
This could happen when there is no financial interest in finding the root cause and there is no great option for treating the symptoms
They didn't even mention Hari Shankar: https://forbetterscience.com/2023/12/20/in-bed-with-hari-and... The field must be rife with fraud and manipulation.
No mention of Leqembi or Kinsula? Both FDA approved. And Simufilam that was mentioned was cancelled because of a failed phase III study years ago.
But fair, improved biomarker data does not mean the drug is making any real improvements for the patients especially with the side effects. But it is also well known.
It's not just that one paper may have been wrong; it's that a fragile consensus can redirect billions of dollars and decades of work. Alzheimer's is also a brutally complex disease, so the opportunity cost of narrowing the search too early may have been enormous
Because of almost certainly fraudulent science. See https://www.science.org/content/article/potential-fabricatio.... Research was misled for decades down the path of assuming that Amyloid plaques are causative of Alzheimers, a now disproven theory (there's an association, but that's not the same as causative.)
Scientist Ruth Itzhaki spent years studying a far more promising theory of Alzheimer's: that it's caused by viral infection in the brain, particularly HSV-1, best known for causing cold sores. Most have it, so there are clearly other factors at work, likely related to susceptibility in particular individuals to to the virus infecting the brain and spreading over time. See https://pubmed.ncbi.nlm.nih.gov/34205498/
The implication is that anti-viral treatments are likely to inhibit and potentially cure Alzheimer's. There is already unintended evidence along these lines, both via antiviral drugs and vaccines.
I see several people here who appear to be replying to the headline rather than actually reading the article (well, podcast transcript, technically). What you mention is already discussed extensively in the podcast episode, and Matt Shrag (the scientist your first link is about) is the one being interviewed in the podcast.
The most complicated known object in the universe, and a disease that attacks the one thing that sets it apart from everything else. No surprise progress is slow in coming.
Given the fertility crisis, you would think that linking a devastating disease to a common and incurable STI would make the both of them top priorities.
Type-3 diabetes? It's degraded endocrine and cardiovascular functionality. Basically, your enzymes stop producing -- things like testosterone and insulin. Your lungs stop working as efficiently, and your brain just gives out.
If you're looking to beat type-3 diabetes, you need to have a daily routine of exercise while you're young to keep these systems in shape when you're old.
You also don't need to belong to any marginalized groups, as ACEs tend to wear your body out over time -- breathing, kidneys, and heart in particular. People with traumatic childhoods (bullying, abusive parents, etc) have a huge risk of dying of dementia -- if their kidneys don't give out first.
Alzheimer’s is a good example of a disease where we don’t have great scientific understanding on the underlying causes, but that doesn’t stop individuals from believing they understand it better than the scientists.
Actual Scientists are calling it Type-3. But these are the same scientists that are actually reversing Type 2 diabetes without expensive drugs. Of course they exist outside the pharma narrative, and they don't have any uncurious attack dogs willing to defend their narrative-busting results.
>and they don't have any uncurious attack dogs willing to defend their narrative-busting results.
Well, they seem to have some champions here...
¯\_(ツ)_/¯ Get curious
This guy brings the receipts https://x.com/markkaplan20/status/2048350831096090749?s=61&t...
True dat. But most of Europe calls it type-3 diabetes, because of the reasons given.
[flagged]
Are recurrent childhood neglect and abuse events not an antecedent to mental health morbidity in adulthood, which then creates missed opportunities for growth and necessitates and the need for the use of medications?
I think you’re making a giant leap from A to Z and missing a whole bunch in between.
All I know is that people with higher ACE scores have higher dementia rates. And that higher ACE scores are linked with heart failure, lung failure, and kidney failure.
Stress ages the body. Homeless people can age several years, being on the streets for just a few months.
I've also seen numerous people in these upbringings die in their 50s and 60s from kidney failure. My stepdad was one of them. My father too.
My father had a normal childhood, except he had a traumatic experience of shooting his twin brother while they were playing cowboys and indians. Spent his entire life blaming himself. Went through all the normal development phases. Not on any meds.
His body just started shutting down prematurely. It's common in people with those experiences. First, his breathing got bad. Then his kidneys. Then he started having heart problems.
And that's the pattern. Heart, lungs, kidneys. Which are all linked to the brain. And eventually lead to dementia-like symptoms. At least that's what the research on ACEs seems to point out.
And the pattern holds in people who suffer excessive bullying, societal excommunication or exile, domestic violence, or social stigma.
Marginalized people have a high death rate in their 50s and 60s, because of societal bullshit -- no other factors needed.
Are those things not linked to cPTSD,
which is linked to nervous and endocrine dysfunction,
which is linked to Alzheimer’s/Dementia?
> your brain just gives out.
Meaning, failing of the glymphatic (and possibly lymphatic!) systems.
There's progress, just only for those with access and can afford it
The President is singlehandedly kept this side of functional via infusions of this drug each month
https://beingpatient.com/fda-alzheimers-leqembi-nih-memo-tru...
They mysteriously rushed approval despite all other activity suspended the week after he was sworn-in
Watch how he disappears for a few days each month, that's why, it can only be done in a hospital and they have to do MRI for leakage
I think saunas and heat-shock proteins are harder for pharma to put in pill form.
One important researcher fabricated data that directed too much funding to the amyloid hypothesis.
Next question.
I'll say that I know nothing about this, but just commenting on the economics of it all: Cancer and HIV have been at the forefront of disease research, in terms of public interest and financial investment, and cancer is more like an umbrella of similar diseases than a single disorder. HIV is manageable these days, and cancer research is slowly seeing leaps in progress.
Alzheimer is very important, and affects a very large number of people, it is getting lots of research funding and attention, but perhaps not enough? If it takes a certain combination of time, human-hours, money, and lots of smart people being interested in doing research in that field. Is the economics of disease research that simple? it is unknown what numeration of those variables is required to tackle Alzheimers, but if it is a lot more than cancer for example, then it might be decades or more away from being well understood.
I hate to say it, but cancer and HIV feel more like things we can get, Alzheimers feels like something only old people get, and it's to easy to forget that we'll get old, and it's hard to think our older loved ones might be affected. If no one in your sphere has been affected, it's harder to prioritize the disease.
My opinion is, money is the biggest obstacle, and I don't mean money for research, but money for education for researchers, and the talent pipeline. If higher education (at least for medicine) was literally free, that'd be a start. then you need lots of people getting paid to do the research independently. Right now, it feels like most disease research is being done by big pharma, so they can find the next insulin they can use to maximize profits. The incentives are all wrong on all sides, for potential researchers, the public and R&D companies.
The potential profits from an Alzheimer’s treatment are extremely high, I doubt it’s being overlooked.
> and it's hard to think our older loved ones might be affected
A large proportion of people don’t need to think about it because they have witnessed the horrific effects on loved ones first hand.
but not as much as cancer or hiv
I can't see why HIV treatment would generate more profit than dementia, that doesn't make any sense to me. Dementia affects a lot more people, and it affects the wealthiest possible demographic. What is your logic there?
> Alzheimers feels like something only old people get
https://en.wikipedia.org/wiki/Early-onset_Alzheimer%27s_dise...
> Nonfamilial early-onset AD can develop in people who are in their 30s or 40s, but this is extremely rare, and mostly people in their 50s or early 60s are affected.
Depending on what you consider "old", this might not change much
An old friend of mine was one of the people working on this. Had access to top10 supercompute time and everything. He never wanted to talk about it, and he'd talk about anything. Said it made him see red. Not long before the news broke, he killed himself.
I'm pretty adamant it was fraud. You don't have to look very hard to see how profit incentives are fucking up the health/medical sector. Check out how often $1000+/dose drug goes generic and within +/- 3 months a study is published that reveals it can be strongly linked to any number of issues that would have caused it to never get approved in the first place. Then you look at the original studies and see they specifically excluded anyone that those problems would have shown up in!
can’t help but see this thread next to the Erdos one and feel like someone’s trying to tell us something :)
It keeps slipping their minds.
...because Alzheimer is a dormant side effect of a virus, not of a messenger chemical. But that doesn't go well in studies and "self populism" of what funded research wanted to hear.
If you study effects and not causes due to lack of measurements for reproducibility in any field of research, that's what comes out.
Also check out how the new and promising correlation started by observing the Wales eligibility for mandatory shingles vaccination during an outbreak and the effect on that test group when it comes to alzheimer or dementia in their old age.
Note that shingles (herpes zoster) virus is a dormant virus for decades, and it's not really treated because of that.
Also note that this was only discovered because people died and their data set was publicized because of that, which I hope that can happen in an anonymous way due to it being invaluable for medical research.
[1] https://www.alzheimer-europe.org/news/analysis-electronic-he...
[2] https://pmc.ncbi.nlm.nih.gov/articles/PMC11485228/
[3] https://www.sciencedirect.com/science/article/pii/S009286742...
[4] https://www.alzforum.org/news/research-news/shingles-vaccine...
Gee, that sure is a confident statement of fact.
Or maybe virus activity is one way that a negative feedback loop involving protein aggregates can begin...
“Complications due to unaddressed microbial infection” will read as pretty confident, too,
but it’s still pretty vague once you’ve really dug in.
That's why I was emphasizing "one way" and "can begin".
Clearly viral infection may be a distal factor but it is not the proximate cause of Alzheimer's... which is quite conclusively due to protein aggregates.
I don’t find any of it conclusive.
Protein aggregates seem like the effect, with many causes.
Yes, exactly. Whether it APOE mutation, traumatic injury, metabolic dysfunction, Herpes infection, or some other inflammation that upregulates kinases, you end up with hyperphosphorylated tau which in turn forms the neurofibrillary tangles that destroy nutrient transport in neurons and eventually kills them.
"Neuron death by protein aggregates" is the best way to define Alzheimer's. Anything more specific refers to only one of those aforementioned causes; anything less is just "brain don't work no more."
These clickbait headlines are so frustrating, especially since the article itself explains the tau mechanism and all the progress that has been made in understanding the disease.
Sure is a line of inquiry worth pursuing either way, no?
It very much has been. Which is why it's tiring to see these articles (and HN comments) portraying it otherwise. Search HN for Alzheimer's and you will find lots of updates on the research and lots of the same uninformed comment threads.
Not always. Genetic causes are known.
... which kind of points to the indicator that "Alzheimer != Alzheimer", implying that too many diseases with the same side effects are categorized together?
A lot of virological and parasitical components have historically been wrongly associated with genetic markers, too. Toxoplasmosis parasite comes to mind.
[1] https://en.wikipedia.org/wiki/Toxoplasmosis
[2] https://en.wikipedia.org/wiki/Toxoplasma_gondii
Non-sequitur
> Non-sequitur
Not sure what you are trying to achieve with comments like this, besides intentional gas lighting.
Could've commented with links to scientific articles or papers that disprove my theory.
Instead you chose to be ... this?
https://med.stanford.edu/news/insights/2025/09/rethinking-al...
You do realize that they are referring to the same study and dataset, which showed that shingles is correlated to APOE4, right?
Not sure if you are trolling at this point.
I am not a researcher in this field. I have read a lot about APOE4, and nearly everything I have seen about APOE4 makes it out to be the clearest of all predictors for Alzheimer's. I get that you're upset that I posted like I did, but I am not trolling. The point was that genetic causes are not an exceptional predictor for Alzheimer's. I had a hard time seeing how the best established predictor for Alzheimer's validates there being too many things labeled as Alzheimer's. If I had posted with a focus on some edge case, then it probably would have made more sense to me, but as I read it, it really seemed like a stretch.
Dropping this thread now. I am fine with being wrong, but my brief posting was not trolling.
Non-diagnostician
Point stands.
So does the lack of a model for Alzheimer’s,
and other chronic illnesses,
that the consumer-facing medical industry prefers to dismiss.
The tau hypothesis is looking like a good model.
I didn't argue a model beyond one cause.
Well apparently you can be a president while suffering it.
Because billionaires haven't gotten it yet, or their loved ones. If Elon or Bezos get it, it'll get funded to kingdom come.
Bill Gates Dad had it and died from it.
We tend to forget
Most of these comments are spot on. We seeded (and continued to fund) the most recently approved Alzheimer's drug on the market about 15 years ago and fought an uphill battle the entire way. The entire industry - other than what seems about a dozen neuroscientists - were fully bought into the plaque scam, and many still are. As I mentioned in a different thread some time ago, the best way to think about plaque is like gravestones in a cemetery. If you remove the gravestones, the dead bodies are still there.
We were introduced to the head of neuroscience at Houston Methodist as part of our due diligence process; his entire career was built upon the removal of plaque from the brain and would not even consider an alternative theory. We ran into this for years. It made funding the trials very difficult. We were totally ignored by all the Alzheimer's charities and orgs (ie Seth Rogan's for example). Only the Michael J. Fox foundation contributed early on.
However, our drug, now known as Zunveyl, was a pro-drug of already on the market Galanatmine, which was the second most commonly prescribed drug in the world for this disease (about $6BN/yr). Our pro-drug almost eliminated the side effects of Galanamine (nausea, vomiting) and enabled us to increase dosage high enough to actually get enough molecules into the brain. It was (is) awesome. Some of our first clinical trials were healthy young adults - they did extremely well. I don't think I can share the actual results but I hope that we (or someone) can fund a study to get approval for "regular people" usage one day given how well this test went. Later tests went just a well but only thanks to the "fast track" program were we able to even get to market.
Even today after being on the market for about a year now, the market uptake is slow due to insurance company approvals. We are getting reorders like crazy but often new patients get denied initially and then doctors have to appeal and then they get approved. This has been taking about 6 months on average and is brutal for people with the disease (and their families). Since getting a drug to patients is actually a (sadly and surprisingly) large sales and marketing expense, the company (Alpha Cognition) is focusing on long-term-care centers for now, but we had always hoped that this would be available much more broadly and much faster. Several of the early investor's parents were alive and afflicted with this disease when we started, but have since passed away. I hope that we can get this out and help others - faster.
The mother company that spun this out is also working on other molecules to try to stop Alzheimer's itself, rather than "only" help with symptoms but as always funding is a challenge. Clinical trials must be done correctly and are thus expensive.
Been living this battle for 15+ years and hoped that this can shed a little light on how things have been.
I have faith on 40hz ultrasound therapies.
because coconut oil and non-usa model diet is the key. and its not making $ for the owners
[dead]
Same scam and politics as the Ancel Keys lipid-heart hypothesis. Complete BS, ego and career protectionism, resulted in the deaths of millions and most people still believe that crap.
[dead]
[dead]
[dead]
[dead]
[dead]
Ok so how does he know that? This whole podcast is about how we don't even know how tau clumps and amyloid build ups relate to the progression of the disease.
You can still buy Oligosol Lithium in Europe.
We just keep forgetting about it!
Now that the “plaques are the disease” folks are having to listen to viable research in contradiction to them, there is a possible outcome that an mRNA vaccine for tooth decay ais also an mRNA vaccine for Alzheimer’s, if that particular theory pans out. Which would subtract a trillion dollars from GDP over a medium timescale. I remain hopeful :) but I’m not particularly holding my breath for the U.S. to invent a cure at this point, simply because of how much profit it will cost the booming industries of health insurance and elder care.
Do you have a link? A biotech company called Cortexyme already tried a drug against P. gingivalis, which causes gum disease, based on the idea that these bacteria migrate to the brain (many old people who died of AD have gum disease and tooth loss). But that drug failed phase II/III as there was no evidence of any effect.
Aw, drat.
The science was delayed a decade due to fraud.
Not just a decade
Can u tell me what this is about?
I liked the story as told here in Science: https://www.science.org/content/article/potential-fabricatio...
The amyloid hypothesis and associated fraud covered in the TFA.
Big Pharma refuses to believe that the gut microbiome plays a significant role in human health. They either don't take it seriously or think it's so complex that it's not worth working on. I think they're totally wrong and that the microbiome is the arbiter of not only Alzheimers but cancer and other metabolic disorders like T2 Diabetes.
Regardless of what you believe, the idea that big pharma doesn't believe in gut microbiome playing a significant role in human health is absolutely wrong as easily seen by the rise of GLP-1 drugs (which affect gut microbiome) and are the blockbuster drugs "big pharma" is investing heavily in currently. Perhaps, go take a look at that.
GLP-1’s are a weak counterpoint. Perhaps go take a look at that yourself.
[dead]
What are the 3 pro’s of Alzheimer’s disease? The 3 pro’s of Alzheimer’s disease are: - Every day you make new friends - You can hide your own eastern eggs - And every day you make new friends ——- This a a bit of a dark joke that goes around in The Netherlands. In Dutch it goes like this: Wat zijn de drie voordelen van Alzheimer? De drie voordelen van Alzheimer zijn: - je maakt elke dag weer nieuwe vrienden - je kan je eigen paaseieren verstoppen - en je maakt elke dag weer nieuwe vrienden —- The meaning of this joke is not to ridicule patients whom suffer from Alzheimer’s disease. Not at all. It is just meant to make people smile for just an instant. And making them experience a little how Alzheimer’s can affect your brain.
About the question: Alzheimer’s disease is a condition of the elderly, and they’re on their way out anyway. That is what I observe. Healthcare is a moneymaking business. In capitalism. While it should be free. And excluded from patenting or copyrighting. Healthcare has turned into wealthcare. No wealth? Game over. No extra life for you. On the other hand, maybe the subject is just so complicated for today’s scientists. It is all in the eye of the beholder. The existence of F1 racing cars doesn’t mean that Tesla will never be part of Formula One’s future. As we speak there’s already one Tesla racing through space…
"Alzheimer’s disease is a condition of the elderly, and they’re on their way out anyway." That's a such a protestant way of thinking. It contrasts very much with the catholic culture of southern Europe. I am not saying that is better or worse, but I think it is a very clear example of how different the culture is across the UE. One key aspect is how to look after your elders.
I might sound like a broken record, but dentistry is stuck in the past.
Alzheimer's is basically an advanced form of gum disease caused by Porphyromonas gingivalis) that has infiltrated into your jaw and then traveled into your brain where it causes systemic inflammation which in turn lets other pathogens in that cause neurodegeneration.
There is probably no cure because the only thing you can do in dentistry is prevention and preventative dentistry is still in its infancy.
This is probably wasted on the HN crowd though, because I haven't seen any demand for preventing Alzheimer's.
It may be one source of the disease, but it is almost certain it isn't the only source.
It is a "There is No Antimemetics Division" kind of scenario. They discover the cure and then keep forgetting it.
The company I work at has been building a dementia prevention program covered by most insurance plans in the US. Our clinicians work directly on helping understand risk of neurodegenerative disease and help tailor personalized plans to improve outcomes. A recent lancet study concluded that around 45% of dementia cases are preventable [0] Happy to answer any questions people have.
https://www.betterbrain.com
Disclaimer : I work as the CTO at BetterBrain
[0] https://www.thelancet.com/commissions-do/dementia-prevention...
What is your approach towards nutrition ? Meaning which exact diet do you expect to help in mental health?
Different person, unrelated to the above advertisement but:
Sometimes any diet.
Mental health struggles can exacerbate, (and be exacerbated by!) forgetting to eat, not wanting to eat,
forgetting or passing up the things that keep you in homeostasis, choosing the less correct things because of an emotional response, a physiological response in a “diminished” state.
I asked because I already know the correct answer, which is "metabolic psychiatry", meaning versions of keto/carnivore/epilepsy-keto diets (the latter is the strongest).
Context for old people in assisted living: https://www.metabolicmind.org/resources/news-views/podcasts/...
What things do you focus on to lower that 45%?
I have a kind of outlandish hypothesis that needs more research before it can be taken seriously, but it basically says that the cause and effect are backwards. Mental atrophy due to less learning/thinking, isolation, loss of meaning and purpose happens first. The sleep down regulation and decay of mental circuitry comes after. Would explain why treating the physical symptoms doesn't work.
Protective against the problem is anything which keeps you mentally active, such as socialization, work, religious community participation, hobbies, and meditation. Retirement, death of partner, isolation, sleep deprivation, depression, dissociation, psychosis, medications/drugs which interfere with restful sleep increase risk.
A possible falsification of this hypothesis would be if it's caused by inactivity or physical self neglect, as those often go hand in hand with the correlated and anti-correlated factors mentioned above.
This is particularly interesting:
> Intriguingly, studies show conscientiousness and neuroticism to be associated with Alzheimer’s disease and related dementias but not with their pathologic hallmarks such as plaques, tangles, infarcts or Lewy bodies in the brain.
https://pmc.ncbi.nlm.nih.gov/articles/PMC7484344/
> Mental atrophy due to less learning/thinking, isolation, loss of meaning and purpose happens first.
Except early onset Alzheimers happens and it also happens to plenty of people for which none of those are true.
I mentioned this could be a possible falsification of the idea. It's also possible there are multiple causes and the modality I mentioned is a cause for some. I'm not sure. There are definitely cases where isolation contributes to cognitive decline.
Exactly. My mom lost her job because of early onset. She was very social, read tons of books, etc…. Now, I’m happy she at least still knows who am, but she can’t put a sentence together.
Example: Claude Shannon
This isn’t a hypothesis, it’s a wild unsubstantiated guess
A hypothesis is an unverified tentative insight into something which could be true. Current research is correlating dementia with a wide variety of areas including even personality typologies which are nothing more than statistical clusters of observations.
What I did when I stated this is looked at a number of observations from current literature and asked a what-if question. People unwilling to ask these questions are blinding themselves to entire areas of possible explanations. My hope when posting this was that people might engage with the idea instead of calling it a guess. Retirement, isolation from pandemic lockdowns, isolation from solitary imprisonment, and isolation from death of a partner are all associated with cognitive decline.
There's enough correlation here that it would be worth researching. That's all I am saying, I am specifically not saying my claim is factual just that it is a possible explanation that if true would explain a lot.
Its done substantially better than more common diseases like ME/CFS which very few have even heard of let alone know the symptoms of and receives almost no funding at all. Alzheimer's received a further $100 million of NIH funding earlier this year (https://www.alz.org/news/2026/100-million-dollar-alzheimers-...). That is 6 times the total funding for ME/CFS federally which is currently just 15 million and planned to decline.
The research went awry in Alziemer's due to fraud but its being funded at a reasonable level, a level many with Long Covid or ME/CFS or Fibromylgia would be very happy to see but doubt will ever happen. Funding of diseases is not "fair", it isn't based on number of sufferers * quality life years lost and we should be spending more on medical research generally. Alzeimers is one of the better funded diseases in the world.
It is a crime and a tragedy how criminally underfunded ME/CFS is.
I'll probably be downvoted for this, but I honestly think quality of life of CFS is lower than Alzheimer's.
I truly wish that disease funding was based on science and metrics rather than marketing and vibes.
That being said, Alzheimer's absolutely deserves it's funding and it is very sad to see setbacks related to fraud.
[flagged]
> long COVID is probably more accepted as a real thing by practitioners at this point than CFS
Isn't long covid just CFS that can be attributed to Covid?
If you accept that multiple viruses can cause "long <virus>" syndromes, of which long covid is just one example, it's plausible that CFS is really a cluster of syndromes, one category of which is these post viral syndromes. We just can't pinpoint the virus behind it every time because most viruses haven't been studied as much as Covid has.
I don't know why you're being downvoted, your comment is spot on.
It is understandable for being downvoted in an off-topic discussion about ME/CFS in an Alzheimer's hacker news post.
But I believe the reason he is getting downvoted is because much of it is objectively incorrect, and people who live with ME/CFS don't have energy to go in depth to give a detailed reply.
I've replied with a more in-depth post where I cite studies that debunk many of the claims. (https://news.ycombinator.com/item?id=47914956)
I appreciate your interest in this topic, but respectfully, many of your points are incorrect.
ME/CFS is real. [1][2][3] Alzheimer's is terrifying, but I don't believe it is fair to say that it is obviously more terrifying than ME/CFS. People with ME/CFS have an abysmal quality of life. [4][5] And finally, ME/CFS is significantly underfunded by an orders of magnitude across all metrics, even when you account for the some of the concerns you raised such as dollars per patient, dollars per year lived with disability, etc. [6][7]
For those who haven't heard of ME/CFS, let me give you a high level summary.
We are all fatigued in this day and age, but fatigue isn't sufficient to describe what it is like living with ME/CFS.
At mild severity you are so fatigued that you have to decide between showering or doing laundry as your one physical activity for the week. But if misjudge and overexert yourself, it can take days or weeks before you get some of your energy back, assuming it ever does. Overexertion risks permanently decreasing your energy capacity.
As ME/CFS progresses in severity, the more comparable your life becomes (subjectively) comparable to someone with Locked-in syndrome. You become unable to talk and walk. Even looking at colors and hearing loud noises can be too much exertion, leading many people to wear earplugs and blindfolds for all hours of the day for months/years at a time. You have no choice to lay unmoving in bed all hours of the day with nothing but your limited thought capacity to keep you company. ME/CFS is currently incurable and virtually untreatable, but usually isn't fatal. It is possible that the disease eventually gets so severe that breathing and beating your heart is too much exertion, but that is almost unheard of. You have to live like that for rest of your life.
You are surrounded by people who don't even believe in the disease, and getting disability benefits is borderline impossible.
This disease isn't even rare - estimates are between 1-3 million people in USA alone. That's roughly 1 in 100 to 1 in 300.
Studies showing CFS is a real biological illness (there are plenty more, too many to list here) [1] https://www.mdpi.com/1648-9144/60/1/83 [2] https://pmc.ncbi.nlm.nih.gov/articles/PMC6787691/ [3] https://www.nature.com/articles/s41467-024-45107-3
Studies about MECFS quality of life: [4] https://pmc.ncbi.nlm.nih.gov/articles/PMC11356561/ [5] https://pubmed.ncbi.nlm.nih.gov/26147503/
Studies detailing how grossly underfunded CFS is [6] https://pubmed.ncbi.nlm.nih.gov/32568148/ [7] https://www.nature.com/articles/s43856-026-01516-7
[dead]