[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.

[john_strinlai]

>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.

[DavidSJ]

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.

[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-...

[DavidSJ]

As noted elsewhere in this thread, which you seem not to have read, I discuss that matter in the article, which you also seem not to have read.

[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.

[DavidSJ]

Those are amyloid-only mice. It's an amyloid+tau disease, with tau the proximate cause of neurodegeneration. Normal mice don't get tau pathology, whereas even healthy human beings do, however it stays localized until the presence of widespread amyloid pathology.

Causal intervention on amyloid+tau mice is consistent with causal mediation from longitudinal human neuroimaging data: the amyloid pathology greatly accelerates tau pathology, and then this causes neurodegeneration.

[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.

[DavidSJ]

The hypothesis that amyloid is simply a downstream effect, not a cause, is of course worth considering, and where my mind was at when I first approached the literature skeptically. The widespread presence of amyloid-beta plaques in Alzheimer's disease has been known since 1906, but the field didn't adopt the amyloid hypothesis for decades precisely because of this possibility. But then in the early 1990's, strong genetic causal evidence emerged, which is why the amyloid hypothesis emerged at that time. Other important causal evidence has emerged since, especially that tau pathology (the proximate cause of neurodegeneration) is causally downstream of amyloid pathology, which we know from many lines of evidence now. (See the article for a lot more detail on all this, if you are curious.)

As for the possibility that the successes of amyloid therapies might be explicable by chance, this is highly implausible. Only three (aducanumab, lecanemab, and donanemab) of a dozen or more amyloid therapies successfully cleared plaque, and it is precisely those three that achieved a slowdown of cognitive decline in phase 3 trials (with aducanumab succeeding in only one of its two, but with the others succeeding in their only phase 3), several of which with p-values below 0.001. This is not p-hacking or reporting bias.

[DaveZale]

Yes, and the fact that something like oral hygiene can influence AD would support your thesis. Often an infection in the gums/teeth can result in boils or worse in distant parts of the body. Add a dysfunctional blood brain barrier and you are screwed.

Brush and floss bruddahs.

[laughing_man]

Amyloid plaques could be part of a disease cascade. Not the root cause, in other words, but an additional downstream problem than probably still needs to be addressed.

[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.

[DavidSJ]

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.

A few years longer. It's obviously frustratingly far from where we'd like to be. It was only a direct response to the claim that Alzheimer treatment isn't even in the "sometimes progress is slow" category, but rather in the "no meaningful benefit at all" category.

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

We agree that people should be willing to entertain other ideas! I don't think anyone is saying otherwise.

[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...