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Discussion (58 Comments)Read Original on HackerNews
In the words of Derek Lowe:
Amyloid-directed therapies truly, truly do not appear to be the answer for Alzheimer’s treatment. When I started work in the field back in the early 1990s, I was convinced of the opposite - the evidence looked very strong that defects in amyloid processing were indeed the cause of the disease. But that was thirty-five years ago, thirty-five years in which therapy after therapy after therapy aimed at amyloid mechanisms has failed.
[…] We’re way past persistence, way past focus, way past optimism and multiple shots on goal and old-college-tries. Do something else! For God's sake, do something else.
— https://www.science.org/content/blog-post/anti-amyloid-antib...
I don't have a dog in this fight and I don't remember that much but I read someone's "in defense of the amyloid hypothesis" with interest. So if you want an counterpoint, you can go read https://www.astralcodexten.com/p/in-defense-of-the-amyloid-h...
"I am David Schneider-Joseph, an engineer formerly with SpaceX and Google, now working in AI safety. Alzheimer’s isn’t my field, but I got very interested in it, spent six months studying the literature, and came away believing the amyloid hypothesis was basically completely solid. I thought I’d share that understanding with current skeptics."
6 months of reading literature when you don't know how to read biomedical literature isn't very confidence inducing. I know this site really likes it when smart outsiders come in and disrupt the status quo, but... probably not in this case.
To be clear this isn’t about whether it’s right or wrong it’s about that science involves investigating all avenues with evidence, proof, and rigor. Group think is how we end up incorporating bias into science, which is anti scientific.
But again I am not saying you are wrong and I am even sympathetic to this narrative but ultimately, unconvinced, either way
> The 2006 paper suggested an amyloid beta (Aβ) protein called Aβ*56 could cause Alzheimer’s.
https://www.science.org/content/article/researchers-plan-ret...
If the accusation is "the field has been captured by a group with a vested interest in a model based on fraudulent research, strongly biasing what gets funded and what gets published" I wouldn't expect "studying the literature" to be particularly helpful in assessing the claim. It's sort of like saying "I read all of Enron's press releases and SEC filings, and they sound legit."
The defense reads more like a special pleading or sunk cost fallacy. There has been a lot of research done on one hypothesis, actively excluding alternatives, so that hypothesis deserves to be considered until disproven (he does, iirc, allow for a test that would de-privilege the amaloyd hypothesis).
Isn't the current thinking that amyloid-beta buildup is a marker, not a cause? The therapy may be working here, but it isn't clear whether clearing amyloid-beta proteins is the mechanism or an outcome.
Don't get me wrong, if you are in this area of research this debate is important. There may be other types of Alzheimer's that have a different means. This drug may actually target something else. There might be some other truth I haven't thought it - but to me as an outsider the important part is a treatment that works, not why it works.
There are dozens of studies that show mice improving their memory/spatial reasoning as Alzheimer's models. None of them have led to a proven improvement in longevity or quality of life for human Alzheimer's patients. Some of them slightly slow the progression, but even then you're getting into a gray area - is it really "better" to be stuck in the Alzheimer's fog for longer? Are we actually improving quality of life? It's unclear.
So no, in order for us to say that this approach "works", we would need randomized controlled clinical trials in humans showing a strict improvement in quality of life and/or longevity. This is not even close to that level of evidence.
So there's some benefit. Sounds like their next step is a much larger trial to answer the question you are posing.
The problem is that claimed success in these rat models has never transferred to humans. Either the problem is that rat Alzheimer’s is a poor model for human Alzheimer’s or the science being done is poor quality.
> Because reducing amyloid burden is clinically proven to improve functional outcomes, these preclinical results strongly support the rationale for testing this drug in early symptomatic Alzheimer’s disease
I believe this is the critical criticism of others. There’s now two camps. One side claims that the Amyloid movement is based on faulty science and outright fraud (true AFAIK) and the other side claims that there’s still evidence the amyloid hypothesis is accurate despite the flawed start to the hypothesis (possibly true). Generally I don’t trust a lot of effort being pushed behind a hypothesis that’s got such shady behavior from proponents and that rely on fast tracking drug approvals for drugs that reduce amyloids but clearly don’t benefit Alzheimer’s. Everyone gets to choose the priors they choose to evaluate the situation on.
That has stopped, presumably, but alternative approaches haven't had much success yet either.
Given the decades of emphasis on clearing / preventing amyloids I would be fairly jaded. If someone (biotech) wants to spend $$$ chasing this down, good on them.
But a paper curing a mouse model of a human neurological disease does not move the needle for someone with or watching someone suffer from this disease.
The TLDR is that the researchers were publishing doctored images to support their hypothesises, which is why the Amyloid hypothesis was such a dead end.
Maybe there’s some way to get around this particular issue.
I don't see why this is definitely doomed just because they discuss beta-amyloid plaques. Those exist and are real. They probably don't cause it any more than tombstones cause graveyards; very related, but not in the directly mechanistic way we wish.
> Alzheimer’s disease (AD) is a prevalent neurodegenerative disorder characterized by the accumulation of amyloid-beta (Aβ) peptides in the brain.
This can be true and still not be the specific mechanism.
You can treat a specific waste product or you can repair the waste stream. The issue may be waste, but not a specific product, or the issue may not be the waste stream at all.
This work appears to demonstrate evidence of waste stream repair via a well-known waste-product. That doesn't mean that any specific waste product is or is not the problem or that this particular stream is definitely going to remove enough of the waste (if that was the problem).
Maybe there have been a lot of drugs which have similarly attempted waste-stream repair so there's good reason to doubt it on that alone. But I don't think that mentioning beta-amyloid plaque is enough to discard this out-of-hand.
For humans, not yet progressed to trials though safety has been evaluated for other diseases, so possible for trials to happen quickly?
" the compound has strong potential to quickly transition into human clinics because it has already undergone safety evaluations for other diseases."
What makes alzheimer's difficult is that it is not really a single uniform disease. There are subtypes.
Since my mother has it, I was presented with an option of a genetic test. There are several genes which increase your risk. However, if one has PSEN1 that will 100% guarantee early onset alzheimer's at some point.
I'm still on the fence if I want to know.
I really hope we get some viable treatments for this terrible disease. Early onset azlheimer's is awful. I cannot imagine having malfunctioning brain.
Many people without dementia show amyloid plaques in their brains in autopsies. It's becoming more accepted now that there are multiple interrelated causes after decades pursuing the simplistic amyloid plaque theory.
The article is bordering on irresponsible.
Over time, everything breaks down. If this actually fixes some plumbing issue that would be great. Of course, it probably will lead to another downstream plumbing issue, but one thing at a time.
they found people who use glucosamine (joint pain, knees etc)
have a 25% higher chance of Alzheimer's progression
https://thesciverse.org/scientists-found-that-a-supplement-t...
(still can't figure out if that website is "AI" but they have great articles)
> Glucosamine mimicked the effects of a low-carbohydrate diet in a prior animal research, resulting in increased lifespan [21], and studies consistently showed that a low-carbohydrate diet protects against dementia [22, 23]. An animal study suggested that glucosamine may promote cognitive function by impacting energy metabolism [20]; other animal models have indicated the neuroprotective and anti-neuroinflammatory effects of glucosamine
https://pmc.ncbi.nlm.nih.gov/articles/PMC10052856/
That's the predominant theory, but nothing affecting them has yet proven to be efficacious so far (AFAIK).
Likewise, at one time everyone "knew" aluminum was a culprit, because it showed up in autopsy analyses of affected people. However, it turned out that correlation wasn't from aluminum causing it, so avoiding aluminum didn't affect the disease.