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 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.
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.
>> 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.
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.
"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...
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.
> 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.
> 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.
> 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!).
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".
> 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...
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?
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.
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.
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.
"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).
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 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.
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.
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.
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.
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.
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 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>.
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.
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).
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?”
'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.
> 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 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
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 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.
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.
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.
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.
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.
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.
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.
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.
> 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
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.
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.
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.
...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.
... 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.
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.
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.
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.
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.
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.
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.
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.
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 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.
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.
half the stuff currently in clinical trials is not targeting amyloids.
https://alz-journals.onlinelibrary.wiley.com/doi/10.1002/trc...
>> 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.
>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.
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.
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...
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. :)
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.
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
> We don’t even know what all we don’t know.
Somewhat ironic given the context.
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.
This comment is so needlessly aggressive and argumentative. I hate this about HN
> 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.
> 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.
> 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!).
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.
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".
> 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.
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?
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.
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.
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.
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?
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).
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
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.
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.
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/
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.
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.
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.
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.
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>.
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.
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).
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.
The "premature aging" framing makes sense, but I wonder if it risks hiding the disease-specific parts
Grand Unified Theory:
Low intracellular ATP/GTP.
https://www.science.org/doi/10.1126/sciadv.adq6077
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?”
'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?
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.
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
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 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.
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.
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.
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.
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.
We tend to forget
"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.
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.
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...
> 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
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 have faith on 40hz ultrasound therapies.
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.
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.
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.
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 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...
Sure is a line of inquiry worth pursuing either way, no?
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
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.
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.
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.
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.
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?
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.
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
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.