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.

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...

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.

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.

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).

"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.

> 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/

I am working with invitae to get her DNA tested. Unfortunately, her stage is considered moderate and very little treatment options.

> 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...

But again I am not saying you are wrong and I am even sympathetic to this narrative but ultimately, unconvinced, either way

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.

Are you a mouse, perhaps? We already have a plethora of treatments for mice suffering from human-induced Alzheimer's. None of those treatments have ever been shown to work for human patients, and this one is no different.

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.

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.

BTW, many physics people pick up the mechanical bits of machine learning/AI very quickly since they have all the foundational mathematics. The harder parts are understanding all the methods/tricks/complexity that got us to the state of the art- similar to biomed, you just sort of have to immerse yourself amongst knowledgeable people and let their knowledge diffuse in.

Is putting your thumb on the scale against Lowe. When a few replies down from here some commenters have provided an article demonstrating the exact fraudulent science in favor of what Lowe is saying.[0] It seems you may very well be disrupting it because he has a minority opinion. So you’ve possibly spent 6 months understanding an incorrect and fraud supported thesis. That seems like an outsider trying to disrupt it by using their “Google/SpaceX” creds to claim authority on the work of insiders.

[0] https://news.ycombinator.com/item?id=48544407

From a Lakatosian perspective, the amyloid hypothesis is not necessarily wrong, but it is not paying off in terms of empirical insights relative to the amount of attention and funding it has received.

https://a.co/d/0cXTgHgv

So there's some benefit. Sounds like their next step is a much larger trial to answer the question you are posing.

That has stopped, presumably, but alternative approaches haven't had much success yet either.

2. I would never want anyone to believe what I say because of "Google/SpaceX creds" (I didn't even write that line, Scott added it, and only to provide a brief biography and acknowledge that I do not work in the field, not to lend an air of authority to my words).

3. There's no need to cite the fraud to me, since I already discuss it in my article. You are welcome to read that article and form your own opinion about the arguments therein.

If your view is merely that there is a "camp" of experts that disagrees, then sure, but in that case, I do not think it is honest to frame this as a choice between believing in the authority of a single expert from that camp, vs. the (lack of) authority of me, a non-expert.

(I also think your read of the evidence is wrong, but I won't restate the arguments in my article.)

You are correct that a series of clinical trials, which would take 7-10 years, would clear things up. But for now, we simply don't know.

In mice. This is a repeating trend in Alzheimer's research, where the amyloid-beta treatment works in the mouse model but not on humans, because the mouse model induces the amyloid-beta issue (mice don't really get Alzheimer's) and then we treat it.

Sure, maybe an eventual useful Alzheimer’s therapy will remove amyloid deposits, and maybe it won’t, but it needs to actually treat or at least meaningfully slow the actual disease.

Also, I didn't say anything about the evidence (I don't have a "read" on the evidence, because I don't read Alz literature). My point is entirely that my priors indicate that Derek is a more reliable reader than you.

>I don't have a "read" on the evidence, because I don't read Alz literature

these two sentences seem contradictory to me. i am not sure how you would keep up on the research (to know it's moved from majority-held to minority-held view), and know that the move is not reflected in the literature, without reading the literature.

Why do you continue to frame this as a choice between a single cherry-picked expert's opinion, and my own non-expert opinion? Either fairly represent the spectrum of experts' views, or decide based on the actual evidence and arguments.

The raw literature for alzheimer's, as well as biomed in general, is not really easily interpretable. It's rife with errors, misleading statements, and intentional obfuscation.

I've seen this happen before, btw- overturning establishment paradigms, especially ones where the underlying etiology is complex- is extremely hard and often takes decades of experimental results.