7 ms·

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

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-hypothesis https://www.astralcodexten.com/p/in-defense-of-the-amyloid-h...

fnordpiglet 4mo 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 4mo 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
- a_conservative 4mo 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-retract-landmark-alzheimers-paper-containing-doctored-images https://www.science.org/content/article/researchers-plan-ret...
- uxhacker 4mo 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)
  - jjtheblunt 4mo ago
    Proofs and Refutations is a great book https://a.co/d/0cXTgHgv https://a.co/d/0cXTgHgv
  - biomcgary 4mo 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/ 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.
dekhn 4mo 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.
- selimthegrim 4mo 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 4mo 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 4mo ago
  I'm pretty sure there's an xkcd for this.
- 4mo ago
MarkusQ 4mo 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).
- ohbleek 4mo ago
  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.
giantg2 4mo ago
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.
AussieWog93 4mo ago
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.
reinitctxoffset 4mo ago
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 4mo ago
  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-work-dioxygen-difluoride https://www.science.org/content/blog-post/things-i-won-t-wor...

fnordpiglet 4mo 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 4mo 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
a_conservative 4mo 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-retract-landmark-alzheimers-paper-containing-doctored-images https://www.science.org/content/article/researchers-plan-ret...
uxhacker 4mo 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)
- jjtheblunt 4mo ago
  Proofs and Refutations is a great book https://a.co/d/0cXTgHgv https://a.co/d/0cXTgHgv
- biomcgary 4mo 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/ 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.

dekhn 4mo 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.

selimthegrim 4mo 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 4mo 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 4mo ago
I'm pretty sure there's an xkcd for this.
4mo ago

MarkusQ 4mo 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).

ohbleek 4mo ago
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.

giantg2 4mo ago

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.

AussieWog93 4mo ago

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.

reinitctxoffset 4mo ago

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 4mo ago
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-work-dioxygen-difluoride https://www.science.org/content/blog-post/things-i-won-t-wor...