Why has there been so little progress on Alzheimer's disease?
freakonomics.com156 points by chiefalchemist 5 hours ago
156 points by chiefalchemist 5 hours ago
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...
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.
Point number 1, either you were not able to realize yourself that you yourself made the exact logical flaw I was telling, self evidently within the sentence.
Point number 2, either you naively looked up some fact thats incomplete (which any gpt would have clarified if you wanted) or you deliberately swallowed the nuance which in my opinion fully invalidates the argument anyway.
Both suggest you are at best someone who's just looked up some pro Amyloid blog and are saying it back here, or worse, youre actively trying to defend the theory in bad faith as the entire field has done for decades.
It was not fraudulent, just incompetent. Not just here (though this is likely the most egregious example), there are many very bad biological models in circulation even today simply because some dudes who are thought leaders decided these things were this way when there was no causal evidence for it (it was almost always correlation). Thats right, our top scientists of the day still cant fundamentally fathom "correlation =/= causation"). Past examples include "a differentiated cell cant go back". Persistent examples include "longer telomeres cause you to live longer" and "there are x hallmarks of cancer."
And before someone says, "well theres nuance to it," "in hindsight its easy," "biology is complex," my answers are, no no and no. Debate me. Ill bring receipts.
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.
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?
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.
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.
Reminds me of schizophrenia. A hodgepodge of different things lumped into a single label of "broad class of things we don't understand"
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 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.
Disclaimer : I work as the CTO at BetterBrain
[0] https://www.thelancet.com/commissions-do/dementia-prevention...
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.
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 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.
> 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.
'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.
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.
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.
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.
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.
> Alzheimers feels like something only old people get
https://en.wikipedia.org/wiki/Early-onset_Alzheimer%27s_dise...
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.
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...
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.
Which is about Parkinson's, not Alzheimer's, and did lead to some new science.
"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...
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.
We just keep forgetting about it!
...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...
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]
The science was delayed a decade due to fraud.
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...
It is a "There is No Antimemetics Division" kind of scenario. They discover the cure and then keep forgetting it.
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...
True dat. But most of Europe calls it type-3 diabetes, because of the reasons given.
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.
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.
No clue why you think chronic fatique syndrome and dementia ought to be treated as equally debilitating or serious by the medical community, but I'm sure you're the only person on this earth who holds that opinion.
Naturally, the far more terrifying and inexorable disease that is incurable and robs people of their entire personality and will affect most of us to some extent (dementia, if not Alzheimer's specifically) by the end of our lives gets more funding and attention, as it should. The way Alzheimer's has been researched and funded is diabolical, though, but you might pick any other of 200 serious progressive neurological disorders that are underfunded and underrepresented over... CFS. CFS isn't even fully accepted as a syndrome at this point - long COVID is probably more accepted as a real thing by practitioners at this point than CFS.
> 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.