[xitrium]

The last thing I read about the link between amyloid-β accumulation and Alzheimer's was that the entire field was full of fake data ( https://www.science.org/content/blog-post/faked-beta-amyloid... ). In particular, even treatments that directly reduce amyloid-β in the brain did not restore cognitive abilities.

At least this paper tests both cognitive abilities as well as "amyloid-β pathologies." I'm not at all an expert in this field but gold nanoparticles sounds like something you'd see on a late night infomercial, lol.

[epistasis]

In a massive field, one researcher does not constitute "full of faked data," despite how concerning it is.

The problem is viewing individual papers as the unit of truth in science. The "self-correcting" nature of science will actually reject entire papers, and entire directions of inquiry. Including, maybe, a casual relationship between beta amyloid and AD, but maybe not.

The other key part of science is holding everything in a state of uncertainty. There's some "facts" but mostly just hints and clues. And with Alzheimer's disease in particular we are trying to make progress with completely inadequate vision; we really can't even measure so much of what we want to measure. Feynman said it back in the 1960s, too, physicists have failed to deliver the tools to biologists to really measure what needs to be measured. There have been advancements, and DNA sequencing technology in the past decade has been turned into the most clever sorts of information theoretic microscopy by combining DNA sequences with many other biochemical processes. But we as a species still can not measure a lot of the things we'd like to measure.

[xitrium]

I appreciate your commitment to modernist capital-S Science here :) I'm familiar with how the field ought to work but after working in Andrew Gelman's lab for some years, also with how it can fail us. Here I think the researcher in question has had a much larger impact than you are allowing for. Here's a choice quote:

> Every single disease-modifying trial of Alzheimer’s has failed.

> The huge majority of those have addressed the amyloid hypothesis, of course, from all sorts of angles. Even the truest believers are starting to wonder. Dennis Selkoe’s entire career has been devoted to the subject, and he’s quoted in the Science article as saying that if the trials that are already in progress also fail, then “the A-beta hypothesis is very much under duress”. Yep.

And the original expose is quite interesting if you haven't read it yet https://www.science.org/content/article/potential-fabricatio...

[epistasis]

The hypothesis was under great duress even in 2004, when I took a protein structure course that spent a lot of time on prions and the beta amyloid. Many people have devoted their careers to chasing this down, only one as far as we know published impactful fake data.

However, the particular faked data, despite lots of citations, has apparently not lead to any clinical trials:

> Did the AB*56 Work Lead to Clinical Trials? That’s a question that many have been asking since this scandal broke a few days ago. And the answer is that no, I have been unable to find a clinical trial that specifically targeted the AB*56 oligomer itself (I’ll be glad to be corrected on this point, though).

[epistasis]

I wish to retract this comment, as it was not based on full information. I was going off of the data fr the linked article, but here are many more cases of fraud from leaders in the field:

Marc Tessier-Lavigne https://stanforddaily.com/2023/02/17/internal-review-found-f...

Berislav Zlokovic https://www.science.org/content/article/misconduct-concerns-...

Hoau-Yan Wang https://www.science.org/content/article/co-developer-cassava...

Sylvain Lesné - the researcher from grandparent comment's article

This list taken from Chris Said on Twitter https://x.com/chris_said/status/1724448550493315436?s=46

[brnaftr361]

But he's correct, amyloid plaque theory was founded on bad data. Amyloid plaques as causal agents is unclear, but it was made to appear clear by poisoned data, and many studies conducted afterwards, in good faith, assumed that the information and conclusions were sound. However it doesn't appear to be the case, and instead something along the amyloid beta pathway is more likely to be the true causal factor, and plaques an association. It has spawned something of a wild goose chase in Alzheimer's research and treatment.

[epistasis]

The faked data is not foundational to the field, if we are to believe the article linked from that comment.

> But my impression is that a lot of labs that were interested in the general idea of beta-amyloid oligomers just took the earlier papers as validation for that interest, and kept on doing their own research into the area without really jumping directly onto the 56 story itself. The bewildering nature of the amyloid-oligomer situation in live cells has given everyone plenty of opportunities for that! The expressions in the literature about the failure to find 56 (as in the Selkoe lab’s papers) did not de-validate the general idea for anyone - indeed, Selkoe’s lab has been working on amyloid oligomers the whole time and continues to do so. Just not Lesné’s oligomer.

And

> Did the 56 Work Lead to Clinical Trials? That’s a question that many have been asking since this scandal broke a few days ago. And the answer is that no, I have been unable to find a clinical trial that specifically targeted the AB56 oligomer itself (I’ll be glad to be corrected on this point, though).

[SubiculumCode]

A most eloquent response that needed to be said.

[instagraham]

It's hard to discern discourse in a field one is unfamiliar in, I'd tried with the Alzheimer's fiasco. Here's my tuppence:

The plaques are known to be linked to Alzheimer's, the debunking of one paper that messed with its figures does not detract from the whole body of research. The inefficacy of plaque-targeting treatments may not be proof that the plaques are not causal in nature, only that their damage is not reversible/fully understood.

[Etheryte]

Don't worry, it's not just this field, roughly 70% of medical studies are fake or severely flawed [0].

[0] https://news.ycombinator.com/item?id=37572394

[mft_]

That may or may not be the case, but you're rather detracting from the original comment, either deliberately or not.

The issue in the Alzheimer's world is the possibility that the very disease mechanism concept underlying the vast majority of research and interventional trials into which countless multiple billions have been poured, is incorrect.

Within that space, this is orders of magnitude more fundamental and serious than a flip aside that lots of trials have problems, so who cares about another?

[epistasis]

> the very disease mechanism concept underlying the vast majority of research and interventional trials into which countless multiple billions have been poured, is incorrect.

Not "is incorrect," but might be incorrect. And we almost certainly won't know it is correct until we actually have a therapy.

Those pursuing cures could have waited until there was more solid science, but they and their funders took on the risk, knowing full well that the amyloid hypothesis is not proven.

This is not some indictment of science, this is normal risk taking for a problem that hugely affects society.

[smolder]

> Not "is incorrect," but might be incorrect.

That's why the part you quoted is preceded by "the possibility that".

[epistasis]

But the entire framing of the comment is that the amyloid hypothesis is taken as fact and not possibility, when in fact the core research question is whether it is true or not.

It is the best possible explanation so far, but four decades of research have not reached a definitive conclusion.

An open problem is not a problem for science, that's the fundamental focus of science. The problem is people misrepresenting what science is and what it aims to do.

[mft_]

(Late back to this but) It's far more skewed than you're making out. That the a-beta hypothesis is true, is/was the vastly dominant prevailing belief in the field, to the extent that it hasn't been a question that many 'experts' were willing to meaningfully address.

To be clear: for decades, researchers wishing to pursue lines of inquiry contrary to the a-beta hypothesis struggled for traction and funding, and saw their careers struggle as a result[0]. As such, trying to disprove the a-beta hypothesis was not the core research question for many/most, for long time.

[0] https://www.statnews.com/2019/06/25/alzheimers-cabal-thwarte...

[InSteady]

Ah, the game of telephone.

>For more than 150 trials, Carlisle got access to anonymized individual participant data (IPD). By studying the IPD spreadsheets, he judged that 44% of these trials contained at least some flawed data: impossible statistics, incorrect calculations or duplicated numbers or figures, for instance. And in 26% of the papers had problems that were so widespread that the trial was impossible to trust, he judged — either because the authors were incompetent, or because they had faked the data.

Firstly, this is only from one journal, Anesthesiology. Second, the phrase "at least" indicates that while 44% had some amount of (presumably) flawed data, only 26% of the studies were bad enough to be judged fake or severely flawed by this one (admittedly esteemed) researcher in the field of anesthesiology. It's important to be skeptical and do your homework when you hear sweeping and/or shocking results. It's also important to read carefully, especially with science journalism because it is written for clicks and broad audiences, not to reduce ambiguity and adhere to strict standards of accuracy.

[svnt]

I didn’t go look up the quote but based on your version here it sounds like roughly half (44%) had some kind of suboptimality, and of those roughly a quarter (26%) had serious problems preventing them from being relied on.

That means 11% of the total papers should be discarded, which means 89% of the papers can be used.

[InSteady]

As per usual, science reporting fails to use precise language. It can be interpreted either way, although I think your interpretation is the slightly larger leap based on phrasing. In any case, it is far below the 70% (and not directed broadly at all scientific research) that GP states.

[svnt]

I went and read the article but have not tracked down the original paper.

It is at least 26%, because that was the percentage of studies that provided access to their data that proved faked or fatally flawed.

It may be substantially higher.

[Aurornis]

> In particular, even treatments that directly reduce amyloid-β in the brain did not restore cognitive abilities.

Correct, but this doesn’t constitute “fake data”. It could be that amyloid-β is a marker rather than a causative factor. Or it could be that amyloid-β related damage is downstream, and remove amyloid-β after the damage has been done won’t remove the other damage.

It’s too quick to wave away an entire field because a single theory didn’t pan out. Most medical research proceeds with a lot of dead ends before it is figured out.

[xitrium]

Very true, but it seems like you may not have seen the expose on this field in Science https://www.science.org/content/article/potential-fabricatio...