quadhome
4 hours ago
Alzheimer’s is driven by the buildup of toxic proteins called amyloid-beta.
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...
cassepipe
3 hours ago
This is just one person's (informed I assume) opinion tough. It does sound like common sense but alas common sense is rarely a good guide when it comes down to how the body works.
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...
dekhn
3 hours ago
If I had to choose between Derek Lowe (author of the anti-amyloid-research article who is also highly experienced and skilled in pharma) and Scott Alexander/David Schneider-Joseph (psychiatrist and AI engineer, respectively), all my priors suggest Lowe gives better advice.
"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.
DavidSJ
2 hours ago
This frequently comes up as a critique of my article, but I don't claim to be disrupting the field as a smart outsider. Rather, I looked at the field and concluded that the experts seem to know what they're doing. Derek Lowe is very much in the minority on this matter.
dekhn
2 hours ago
No, he's not (I work in pharma at a company that does basic and applied research on Alz). It's more correct to say there are several camps, but the camp promoting amyloid plaques as the causative/driver for Alz has struggled greatly to come up with evidence supporting its position.
DavidSJ
2 hours ago
Is your view that amyloid is actually a minority view among researchers? That seems completely wrong based on basically every conference proceeding I've viewed and the volume of papers and citations I've examined.
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.)
dekhn
an hour ago
My opinion is that amyloid-as-cause moved from a majority to a minority view over the past few years, but it's not yet reflected in the literature (the entire amyloid establishment isn't going to give up its dominant position easily).
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.
john_strinlai
an hour ago
>My opinion is that amyloid-as-cause moved from a majority to a minority view over the past few years, but it's not yet reflected in the literature
>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.
dekhn
an hour ago
Most scientists who are not experts in their field don't read the literature for a field directly. Instead, they synthesize their opinions about the field by consulting experts, and weighing various sorts of evidence. In my case, I work in an adjacent field and see presentations from scientists, have casual conversations with them, and read the news articles in major journals.
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.
DavidSJ
an hour ago
You said the camp promoting the amyloid hypothesis has struggled greatly to come up with evidence to support its position. What did you mean by that if not a read of the quality of the evidence?
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.
dekhn
an hour ago
My estimate of the quality of the evidence is based on daily discussions with people who work in that field and reading summary articles in major journals. I typically don't read raw scientific articles directly- those are aimed at people in the field. Instead, my understanding comes from a synthesis of expert opinions weighted by my own priors (based on 30+ years in the field). Derek's opinion is now the prevailing one that I hear from a wide range of researchers.
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.
DavidSJ
34 minutes ago
What started as an argument to ignore arguments and evidence and instead rely on authority, seems now to have morphed into an argument that we should ignore the authority of the establishment, because of your own personal assessment of the evidence (which you have not yourself read) and your own personal synthesis of conversations you've had with researchers you've personally come into contact with (despite this being apparently unrepresentative of objective measures of typical researcher opinions).
Arguing from authority really only takes you so far when it ends up as an appeal to your personal experience. I'd rather you either address the arguments directly, or drop the dubious appeal to authority.
righthand
2 hours ago
“Derek Lowe is very much in the minority”
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.
DavidSJ
2 hours ago
1. I don't say Derek Lowe is wrong because he's in the minority. Minorities are sometimes right. But since the parent comment was arguing on authority and my lack thereof, I point out only that one shouldn't cherry-pick one's choice of authorities. Either accept the majority opinion of the experts, or come to your own opinion based on the quality of the arguments and evidence.
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.
selimthegrim
3 hours ago
This really has become the new physics now, right where they think they can invade any given field in six months because that’s how long it’s supposed to take physicists to learn AI
dekhn
2 hours ago
In some ways physics is different from biology and medicine, I do think outsiders to physics can pick up and contribute a bit more easily (although it depends on field). Biomed just has an absolute insane amount of ambiguous knowledge that mostly gets picked up through diffusion across decades of learning. And many of the results in the literature are just wrong (one of the reasons I stopped being a researcher was seeing just how bad the publication record in biology is).
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.
bigbuppo
2 hours ago
I'm pretty sure there's an xkcd for this.
MarkusQ
2 hours ago
> 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.
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).
fnordpiglet
3 hours ago
No actually there’s a large body of quashed research over these decades that went against the prevailing hypothesis. It’s one of the key examples of how peer review fails to consider novel approaches in the face of consensus even if consensus is shown to likely be wrong. The fact the original research driving the consensus was fraudulent at worst made it that much more sad.
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.
cassepipe
3 hours ago
I believe you don't have read the link I posted because its author does address the narrative you present here
But again I am not saying you are wrong and I am even sympathetic to this narrative but ultimately, unconvinced, either way
uxhacker
3 hours ago
Groupthink is very much the scientific method. According to Imre Lakatos the key question is does the group expand knowledge or contract it (very rushed reply as about to catch a flight)
biomcgary
2 hours ago
In Lakatosian terms, the amyloid hypothesis is an example of a degenerating research program that has largely failed to predict new observations and is primarily driven by post hoc reasoning. The hypothesis was rescued by research claiming a significant new observation that was ultimately shown to be fraudulent (https://pmc.ncbi.nlm.nih.gov/articles/PMC12397490/).
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.
jjtheblunt
2 hours ago
Proofs and Refutations is a great book
a_conservative
3 hours ago
An example of fraud in research that contributed to the consensus.
> 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...
dbcurtis
4 hours ago
> Alzheimer’s is driven by the buildup of toxic proteins called amyloid-beta.
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.
avgDev
43 minutes ago
From what I read your statement is accurate. From speaking to people who are going through the new infusions Leqembi and Kisunla get rid of amyloid plaque doesn't mean the decline stops, and if the disease was driven by it then it would stop.
Also, studies show some slowing using these new drugs, but the disease still progresses. Therefore, the plaque is most likely a symptom. It could be the driver in some of the cases though, I think in genetic PSEN1 alzheimer's. I've read a paper discussing issue with the body not removing it and allowing to build up.
bijowo1676
10 minutes ago
I read it somewhere that amyloid plaques were actually defensive mechanism of the body to counter the damage to brain from disease, so removing the plagues makes things worse for patients
https://www.salk.edu/news-release/in-surprising-twist-some-a...
chermi
3 hours ago
Yes. And to anyone paying attention, this has been current since about 2010.
bluGill
4 hours ago
I care what works, not about debate. This seems to work and that trumps any debate about what the real means are.
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.
TaupeRanger
4 hours ago
You are wrong. This paper very clearly does not show that it "works". The debate exists for a good reason - the very thing this paper claims to show is the exact thing the person you replied to was questioning. And that is a central question in all of Alzheimer's research.
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.
dgoldstein0
3 hours ago
> Over 56 days, the treatment reduced toxic amyloid-beta by 42 per cent and improved spatial learning by nearly 44 per cent
So there's some benefit. Sounds like their next step is a much larger trial to answer the question you are posing.
mimicmagnet
3 hours ago
https://pubs.acs.org/doi/10.1021/acschemneuro.6c00252
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.
bluGill
2 hours ago
It is a repeating trend in all medical research. However enough does turn out to work in humans that we eventually make useful progress.
wk_end
an hour ago
In general, sure, but in this specific instance (treating Alzheimer's by clearing amyloid-beta) it's been shown over and over again to not work in humans.
TaupeRanger
2 hours ago
The word "benefit" does not apply here. The only "benefits" patients and families care about are: 1) does the patient live longer, and/or 2) does the quality of life improve in a meaningful way? Amyloid plaques are a surrogate marker, and (as already explained by many people in this thread) have not been established as a causal factor in disease. In fact, some work has even suggested a protective role for plaques. So we do not have enough evidence to say that a 42% reduction in amyloid-beta IN MICE relays any benefit at all to humans.
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.
JackFr
3 hours ago
In fairness to parent, while the article doesn't say the title claims 'restores memories'.
vlovich123
4 hours ago
I don’t think anyone is against a treatment that works, regardless of the mechanism.
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.
projektfu
4 hours ago
If a beta-amyloid therapy eventually makes it to successful trials, there will still be people who believe the argument is already over and the therapy cannot work. The problem identified by Lowe and others is that some amyloid-oriented researchers were not only falsifying data but also acting as reviewers and editors of journals and tanking alternative explanations.
That has stopped, presumably, but alternative approaches haven't had much success yet either.
amluto
3 hours ago
Therapies targeting amyloid deposits has been tested extensively in actual humans, and it indeed removes amyloid deposits. The main problem is that none of the therapies in question usefully treat Alzheimer’s disease.
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.
aBioGuy
4 hours ago
In the title "....in the APP/PS1 Mouse Model of Alzheimer’s Disease"
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.
tremon
an hour ago
> to me as an outsider the important part is a treatment that works, not why it works
Are you a mouse, perhaps? We 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.
gwbas1c
4 hours ago
The podcast "Why Has There Been So Little Progress on Alzheimer’s Disease?" https://freakonomics.com/podcast/why-has-there-been-so-littl... discusses a lot of the academic fraud that lead to people following the Amyloid hypothesis.
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.