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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.

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 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.

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.

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.

'Science progresses one funeral at a time...' It is often the case that an entire field is led by a few influential people and until they leave others can't get the air they need to make real progress.

TLDR: gatekeepers stifled exploration and innovation.

When a topic only has a limited number of experts, those experts become gatekeepers.

Those gatekeepers directly or indirectly control research funding.

Gatekeepers necessarily harbor biases, some right and some wrong, about how the field should progress.

For Alzheimer's, some gatekeepers were conflicted and potentially directed the field in the wrong direction. Only time will reveal AB42's true role.

It's easy to find fault in Alzheimer's.

It's harder to see the general solution to the gatekeeper problem, i.e., how to allocate resources in areas with limited experts.

No mention of Leqembi or Kinsula? Both FDA approved. And Simufilam that was mentioned was cancelled because of a failed phase III study years ago.

But fair, improved biomarker data does not mean the drug is making any real improvements for the patients especially with the side effects. But it is also well known.

It's not just that one paper may have been wrong; it's that a fragile consensus can redirect billions of dollars and decades of work. Alzheimer's is also a brutally complex disease, so the opportunity cost of narrowing the search too early may have been enormous

It's good to expose fraud and it does sound like this set back the field, but "Why has there been so little progress"? - probably because it's very hard? We barely understand how the brain stores memories.

I'm dealing with someone with this disease now and it's absolutely hell.

I 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.

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.

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.

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…

We tend to forget

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.

"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?

I'll say that I know nothing about this, but just commenting on the economics of it all: Cancer and HIV have been at the forefront of disease research, in terms of public interest and financial investment, and cancer is more like an umbrella of similar diseases than a single disorder. HIV is manageable these days, and cancer research is slowly seeing leaps in progress.

Alzheimer is very important, and affects a very large number of people, it is getting lots of research funding and attention, but perhaps not enough? If it takes a certain combination of time, human-hours, money, and lots of smart people being interested in doing research in that field. Is the economics of disease research that simple? it is unknown what numeration of those variables is required to tackle Alzheimers, but if it is a lot more than cancer for example, then it might be decades or more away from being well understood.

I hate to say it, but cancer and HIV feel more like things we can get, Alzheimers feels like something only old people get, and it's to easy to forget that we'll get old, and it's hard to think our older loved ones might be affected. If no one in your sphere has been affected, it's harder to prioritize the disease.

My opinion is, money is the biggest obstacle, and I don't mean money for research, but money for education for researchers, and the talent pipeline. If higher education (at least for medicine) was literally free, that'd be a start. then you need lots of people getting paid to do the research independently. Right now, it feels like most disease research is being done by big pharma, so they can find the next insulin they can use to maximize profits. The incentives are all wrong on all sides, for potential researchers, the public and R&D companies.

I have faith on 40hz ultrasound therapies.

Now that the “plaques are the disease” folks are having to listen to viable research in contradiction to them, there is a possible outcome that an mRNA vaccine for tooth decay ais also an mRNA vaccine for Alzheimer’s, if that particular theory pans out. Which would subtract a trillion dollars from GDP over a medium timescale. I remain hopeful :) but I’m not particularly holding my breath for the U.S. to invent a cure at this point, simply because of how much profit it will cost the booming industries of health insurance and elder care.

I'm surprised that better science never resulted from that lady who could smell it.

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.

Because billionaires haven't gotten it yet, or their loved ones. If Elon or Bezos get it, it'll get funded to kingdom come.

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...

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.

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.

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...

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/

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.