[quadhome]

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]

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]

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]

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]

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]

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]

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.

[kurthr]

Wow, it sure didn't take long to show a complete lack of familiarity in the field. It seems like that's going to be a real weakness with LLMs based on volumes of material that are later discovered to be semi-fraudulent and unmotivated by scientific principals.

https://stanforddaily.com/2023/12/31/blockbuster-alzheimers-...

[pcrh]

I have direct experience of research into Alzheimer's disease, including specifically surrounding the amyloid cascade hypothesis.

The strength of the amyloid hypothesis is that it is currently the only way to unify early onset AD that is caused by mutations in APP and presenilin with the pathology of both early and late set AD.

The weakness is that experimental mice expressing mutated APP do not get neurodegeneration, despite showing amyloid accumulation and behavioral defects.

Mice expressing mutated presenilin in contrast do get both behavioral defects and neurodegeneration, despite showing no accumulation of amyloid.

"Perhaps mice are different" is the usual response/excuse.

This defense is considerably weaker now, given the very modest benefits of removing amyloid from the human brain, as shown in recent clinical trials.

So.... when considered rigorously, the amyloid hypothesis remains to be proven.

However, it will always have its supporters until there is an alternate explation for the convergence of mutations in APP and presenilin on precisely that region of APP that generates amyloid.

[computerdork]

This is of course an older thread, but wanted to ask you, what are the major camps in Alz these days?

...and had also heard about how amyloid research had been based on bad/fraudulent research. One of the biggest scandals was by Tessier-Lavigne from Stanford, correct?

[xenadu02]

Let's put all of that aside for a moment.

When the first drugs targeting HIV arrived the results were undeniable. Yes the drugs sucked for various reasons and yes HIV would evolve resistance. But the data demonstrated a very clear link that these drugs suppressed HIV and suppressing HIV made people live longer. Or consider mRNA and COVID, a great success story where the technology was put to good use and the results are obvious.

On the flip side we have certain cancers like certain breast cancers, melanoma, etc that never had a "wow" moment where some miracle turned them from highly fatal into treatable but we have seen decade after decade treatments improve and survival rates march ever upward such that what were once almost guaranteed death sentences are now often very treatable.

These are two disease treatment models worth keeping in mind. Sometimes major leaps are made. Sometimes progress is slow.

Now if we consider amyloid beta therapies: we have treatments that target amyloid beta with varying degrees of success but at least some show definite reductions in amyloid beta plaques. To the best of my knowledge that has not shown to improve outcomes in Alzheimer's patients to any meaningful degree.

That concerns me and I think justifies some skepticism of the amyloid hypothesis. The data is messy but if amyloid beta were a symptom not a cause that could certainly fit the results we are seeing. That doesn't mean the amyloid beta hypothesis is wrong but I think skepticism of the "state of the art" in the field is warranted given the pathetically ineffective progress made to date.

[DavidSJ]

Now if we consider amyloid beta therapies: we have treatments that target amyloid beta with varying degrees of success but at least some show definite reductions in amyloid beta plaques. To the best of my knowledge that has not shown to improve outcomes in Alzheimer's patients to any meaningful degree.

This is false. They slow down disease progression by about 30%, as measured by cognitive outcomes. This is discussed in the article.

[pama]

I work in drug discovery. For the past twenty years or so, my personal analogy for this hypothesis has been a fantasy story around the days after the bombing of Dresden, when a new civilization suddenly visits Dresden and has no priors about what may have happened there. The aliens see bricks all over the place and assume that the bricks were the cause of the catastrophe. They take great efforts to pick up the bricks and save a couple of lives from the people who were covered in the ruble. The aliens build better systems to pick up bricks in the future and get ready to act next time. When a nearby city gets bombed, they quickly visit and help recover bricks saving a couple more lives. A different civilization could have instead focused on reducing the bombs or detecting and defending against the attacking airplanes.

Our immune systems are complicated, much more so than airplanes and bombs. The amyloid deposits are very likely part of an immune response, and although in principle immune responses going wild are horrible and can be fixed, it is very important to work on identifying and addressing the causal factors of this disease. There have been more therapies tested on the amyloid hypothesis that mere statistical fluctuations could explain away. I don't always agree with Derek, but I'm with him on this one. New ideas are urgently needed here, or this horrible disease will be an increasingly common end state for our aging populations.

[xenadu02]

> This is false. They slow down disease progression by about 30%, as measured by cognitive outcomes. This is discussed in the article.

Perhaps I am just not well-informed but 30% slowdown in progression translates to sufferers have some mild improvement in cognitive tests and live a few months longer.

Maybe it is simply too early to tell but I would naively expect something much more significant. Perhaps this is the sort of thing that requires much earlier treatment to demonstrate better results.

I'm not saying amyloid beta research should be terminated. Merely that everyone in the field should be willing to entertain other ideas.

[FatherOfCurses]

But without any training in experimental methodologies, molecular biology, protein mechanics, pharmacology, or any of the other specialized fields that make up the world of Alzheimer's research, how do you view yourself as qualified to make that conclusion? What body of knowledge are you drawing on to conclude that the experts' reasoning is sound, they are properly controlling their experiments, they are drawing the correct conclusions based on the underlying mechanics? AFAIK even people who do meta-analyses are qualified in the field they are doing the analysis for.

[DavidSJ]

This is a reasonable challenge. I won't and shouldn't be able to convince you that my process was satisfactory, but I'll describe it anyways.

I agree that I don't have the qualifications to check whether, for example, a particular cryo-EM study was conducted properly. But I can check whether those who do have such qualifications disagree on the methodology or findings of that particular study. There's a lively debate within the Alzheimer's research community; it's not hard to find dissenting opinions on just about anything, and I actively seek them out, and when such disagreement exists, I avoid weighting any evidence too heavily, unless the disagreement is about broader matters of synthesis or specific statistical or methodological questions in which my non-biological scientific background permits me to reach my own conclusions.

I am also careful not to heavily weight a single assumption-laden preclinical study conducted by a single lab, for example, but instead to look for "smoking gun"-style evidence, in those few cases that it exists, or to look at the bulk of evidence across many studies from many labs, where the specific conclusions do not seem to be seriously in doubt by experts. In general, I've been skeptical, considering alternative explanations wherever it seemed crucial to the bigger picture, and avoiding trusting anything that seemed like it involved knowledge which was heavily in the weeds on stuff that I couldn't understand. I had a personal motivation to understand the genuine truth here, and enough scientific background that I usually know when I'm out of my depth on a specific matter.

I think it's reasonable of you to say: that all sounds well and good, but I just don't know your process well enough to trust it, and you don't have formal qualifications on the matter, so I'll ignore what you say. I certainly wouldn't expect you to take anything on my authority. I see my article essentially as an act of science journalism, and scientific journalists often lack formal training in the field they report on. You can read it and see if the reasoning makes sense and the evidence is convincing, or you can reasonably ignore it and fall back on expert opinions.

I did the investigation precisely because the majority expert viewpoint was being called into question by a lot of non-experts, and I had a personal motivation to find out, genuinely, whether this critique was warranted. If you don't have that motivation, then it's probably not worth your time to do the same. I did, and I came away satisfied.

[righthand]

“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.

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

[DavidSJ]

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]

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]

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.

[cassepipe]

Fair enough but it's not by Scott Alexander but a guest post by David Schneider-Jospeh

EDIT: They edited their message to reflect that

[plomme]

I don't know anything about alzheimers but I'd hope someone that does would engage with David SJ's points instead of dismissing him on lack of authority alone.

[FatherOfCurses]

Oh FFS what does any knowledge matter any more if we can now say that someone who has no medical training has the ability to turn the entire field of Alzheimers on its head?

[palmotea]

> 6 months of reading literature when you don't know how to read biomedical literature isn't very confidence inducing.

Come on, he's a software engineer, a little reading will give him a shit-ton of confidence.

[himata4113]

Makes me wonder if this is the typical correlation != causation argument where amyloids are produced and are simply a marker/symptom rather than the cause.

[bigbuppo]

I'm pretty sure there's an xkcd for this.

[MarkusQ]

> 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).

[ohbleek]

Thank you for writing out this reply, so I didn't have to. I think that somebody who is not working in medicine or pharma at all would not be able to understand how views have shifted concerning the amyloid-plaque theory. It is largely discussed as a theory that has been tested extensively and has only highlighted our lack of understanding of Alzheimer pathophysiology.

That last part isn't a sidenote, it's the entire reason for discussing the theory.

[AussieWog93]

Somewhat tangential, but when I was doing my PhD there was a bizarre amount of research thrown into testing ML algorithm after ML algorithm at bad EEG data in the hope that we'd be able to magically find a signal from noisy garbage input data.

"Progress" consisted of someone finding a new algorithm that just so happened to get good performance on one particular dataset (but not others).

Everyone knew it was bullshit but did it anyway, because it was easy to convince people to give you grants if you have a sexy, sellable hypothesis and a willingness to handwave away the two decades of prior non-progress.

[giantg2]

If I remember the studies right, removing the plaque doesn't reverse the dementia, and some drugs that show improvements in the dementia don't remove the plaque. There's clearly other stuff going on.

[fnordpiglet]

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.

[a_conservative]

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...

[cassepipe]

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]

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]

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]

Proofs and Refutations is a great book

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

[reinitctxoffset]

Derek Lowe is an extremely well-known and widely respected expert in the field of pharmaceutical drug discovery chemistry.

His series "In The Pipeline" has a cult following of experts and non-experts alike.

He is widely regarded as an authority on the chemistry of Alzheimer's.

For a fun introduction to his work, the "first hit is free" dopamine rush is his "Things I Won't Work With", a masterclass in bringing chemistry to life through the lens of synthesis actively dangerous to person and property.

You'll be up all night.

[klibertp]

He's the guy from FOOF[1]! I didn't immediately make the connection, thanks. Yeah, that series was kind of fun, even if it kind of reinforced my layman understanding that all chemists are explosion nerds :D

[1] https://www.science.org/content/blog-post/things-i-won-t-wor...

[dbcurtis]

> 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.

[chermi]

Yes. And to anyone paying attention, this has been current since about 2010.

[whatisthiseven]

I remember reading about this then and I am no where near the biomedical field.

I almost couldn't believe we are still talking about the same causes of alzheimers 16 years later.

[avgDev]

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.

[armadsen]

My wife’s family has PSEN1-mutation EAD (my wife didn’t inherit it). In that particular case it does seem that the mutated genes relate directly to Amyloid production and clearing, and there are ongoing clinical trials for the use of the new monoclonal antibody drugs in treating it. Two of my family members are in a trial for Remternetug, specifically. There is hope that in that specific case where 1. Amyloid buildup may actually be the cause and 2. you start treating it early, years before symptoms start, disease onset may be significantly delayed. There’s no way to know right now except to try it of course.

[avgDev]

Are you family members experiencing any symptoms of the disease?

I guess if my mother has the gene I will test for PSEN1 at some point, but I am worried about the side effects of the meds. Hope things go well for your family.

[armadsen]

My father in law passed away from it about a year and a half ago at age 64. Two of his kids have tested positive for the mutation. They don’t have symptoms yet (they’re in their 20s and 30s).

[bijowo1676]

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...

[bluGill]

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]

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]

> 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]

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]

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]

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]

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.

[Erem]

> improved spatial learning by nearly 44 per cent

We care about this part

[JackFr]

In fairness to parent, while the article doesn't say the title claims 'restores memories'.

[vlovich123]

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]

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]

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.

[anakaine]

In all fairness the cabal was only busted up in recent years, and it was largely responsible for ensuring that alternate lines of research could never get meaningful funding by denying publishing. So where the amyloid plaque line of researxh has had decades the alternate lines of research are only really getting enough sunlight to begin growing now.

The amyloid plaque cabal has quite likely sentenced tens if not hundreds of millions of people to premature death through their actions by preventing appropriate and alternative lines of research.

[aBioGuy]

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]

> 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.

[yxhuvud]

If you read the actual article you will see this doesn't target the amyloid directly at all, but instead improve the brain/blood barrier and restore normal function of immune system, somehow.

[gwbas1c]

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.

[pfdietz]

Having said that, this therapy could be improving clearing of all sorts of things, not just amyloid-beta. If amyloid is just a misleading side effect, clearing it could also be misleading.