6 ms·

Wasn't it revealed that the research supporting amyloid-beta plaque as the cause of Alzheimer's was fraudulent? https://www.science.org/content/article/potentia

by chc4 11mo ago

Wasn't it revealed that the research supporting amyloid-beta plaque as the cause of Alzheimer's was fraudulent? https://www.science.org/content/article/potential-fabrication-research-images-threatens-key-theory-alzheimers-disease https://www.science.org/content/article/potential-fabricatio... https://www.science.org/content/article/alzheimer-s-scientist-resigns-after-university-finds-data-integrity-concerns-papers https://www.science.org/content/article/alzheimer-s-scientis...

epgui 11mo ago
Yes, in a sense... but that doesn't mean amyloid-beta is an irrelevant therapeutic target. It's a bit more complicated.
jvanderbot 11mo ago
IIRC, it was revealed that treating this as a cause is wrong, it complicates or causes dementia, but is a symptom of something else, not a root cause of the disease. But treating symptoms, esp restoring cognitive function, is a good thing.
p_j_w 11mo ago
I'm not a neuroscientist, but it seems that hypothesis existed before that paper and has more supporting evidence than what's been retracted: https://en.wikipedia.org/wiki/Biochemistry_of_Alzheimer%27s_disease#Amyloid_hypothesis https://en.wikipedia.org/wiki/Biochemistry_of_Alzheimer%27s_...
mjamesaustin 11mo ago
This therapy doesn't target the amyloid-beta plaques. It repairs the blood brain barrier, and then the body is able to clear away the plaques. Their buildup is a symptom of Alzheimers, not the cause. The problem with the amyloid-beta hypothesis was the assumption that these plaques were causing the Alzheimers and that removing them by itself could lead to a cure.
- lukeinator42 11mo ago
  Exactly this. Amyloid-beta plaques and their association with dementia were discovered early on (late 1800s/early 1900s https://en.wikipedia.org/wiki/Amyloid_plaques#History https://en.wikipedia.org/wiki/Amyloid_plaques#History), but the theory that they cause dementia hasn't panned out.
- matthewdgreen 11mo ago
  Whoa there. Is that what’s happening? Cause an alternative theory is cause -> plaques -> cognitive disease. You seem to be arguing cause -> cognitive disease -> plaques, and I’m not sure this research demonstrates that. Does it?
  - celrod 11mo ago
    I think they're arguing Cause -> cognitive disease Cause -> plaques That is, that the same cause is behind both. There may be some arrows from plaque to disease as well (i.e., that plaques also increase disease). I dont know the truth, but just trying to understand/follow Alzheimers news and reading comments.
  - pessimizer 11mo ago
    Why does it seem like they're arguing that? I think that it's supposed to really be: cause -> (plaques = cognitive disease), and the fraud was (cause = plaques) -> cognitive disease. As I took it, understanding that there was a fraud doesn't mean that continually clearing the plaques wouldn't have a good chance of holding off cognitive disease indefinitely.
    - matthewdgreen 11mo ago
      I'm simply arguing that the plaques could be the proximate cause and the problem addressed by this treatment could be the remote cause. The OP is being vague in the way they stated it, but it feels like they're saying the plaques are irrelevant. That doesn't seem to fit what we know: the evidence that cognitive symptoms are downstream of plaques is pretty compelling. I also don't think "fraud" should be used in this discussion at all. With all that said, if this One Weird Trick can clear/prevent the buildup of plaques (and thus the cognitive symptoms downstream of them), that's just a best possible outcome.
shawnz 11mo ago
Here's a good article which explains the remaining arguments in favour of the amyloid hypothesis: https://www.astralcodexten.com/p/in-defense-of-the-amyloid-hypothesis https://www.astralcodexten.com/p/in-defense-of-the-amyloid-h...
amalcon 11mo ago
It's most likely highly correlated, but not causative. That correlation still makes it diagnostically useful, which is how it's used here.
- tremon 11mo ago
  I thought amyloid-β buildup is usually determined at autopsy? That's not really the kind of diagnostic medicine I'm looking forward to. Can it also be determined via brain biopsy?
  - mattkrause 11mo ago
    You can do PET imaging for it--there are a bunch of 18F-based tracers that work reasonably well. It also inversely correlates with Abeta levels in the CSF. Ne Neither of those are particularly easy procedures, but certainly better than a biopsy (and autopsy!) https://pmc.ncbi.nlm.nih.gov/articles/PMC3264790/ https://pmc.ncbi.nlm.nih.gov/articles/PMC3264790/
- JamesBarney 11mo ago
  It's very likely causative. There is just too much evidence for it not to be. All the genes related to amyloid processing are correlated with Alzheimer rates. The most likely theory I've seen is amyloid causes tau buildup which leads to the majority of the damage. And by the time they give anti-amyloid drugs it's too late and the tau is doing the majority of the damage. An analogy would be if you have a hole in your house which leads to getting a rat infestation. Once you notice the rat infestation patching the hole isn't going to solve your problem. The hole caused you to get rat shit on your counter, but by the time you fix the hole it's too late to stop the rats from shitting on your counter.
bitshiftfaced 11mo ago
This article: https://www.astralcodexten.com/p/in-defense-of-the-amyloid-hypothesis https://www.astralcodexten.com/p/in-defense-of-the-amyloid-h... makes a pretty compelling argument for continued research on the link between amyloid-beta and Alzheimer's.
- matthewdgreen 11mo ago
  This article is incredibly informative and I wish the folks in this thread would read it. Doesn’t make the current result any less exciting.
- dcrazy 11mo ago
  Not saying it’s wrong or worthless, but do keep in mind that neither the author not the blog owner is in the medical field. That post is an outsider’s read of the consensus opinion from their investigation of the literature, including an estimate of the strength of that literature formed without expertise in the field itself.
  - larsiusprime 11mo ago
    Scott Alexander is in fact an MD
JamesBarney 11mo ago
There were some important papers that turned out to be fraudulent, but there is a large and broad body of knowledge supporting this link.
JoshTriplett 11mo ago
It's correlated, much as body temperature is correlated with infection. But much like lowering body temperature won't cure the infection, directly addressing the amyloid-beta plaques doesn't seem likely to directly address Alzhimer's. Addressing the actual root cause may also make the plaques go away.
- anon84873628 11mo ago
  FWIW the article says this: >"The long-term effect comes from restoring the brain’s vasculature. We think it works like a cascade: when toxic species such as amyloid-beta (Aβ) accumulate, disease progresses. But once the vasculature is able to function again, it starts clearing Aβ and other harmful molecules, allowing the whole system to recover its balance. What’s remarkable is that our nanoparticles act as a drug and seem to activate a feedback mechanism that brings this clearance pathway back to normal levels,” >... >Normally, the protein LRP1 acts as a molecular gatekeeper, binding to Aβ and transporting it across the BBB for elimination. In Alzheimer’s, this system becomes fragile, leading to Aβ accumulation. The supramolecular drugs mimic LRP1 ligands, binding to Aβ and initiating its clearance, effectively resetting the system and restoring vascular function. So we may be lucky in that addressing the plaques as a symptom does indeed (allow for) repair of the underlying cause. I guess the question is how long the benefit lasts. What triggers the negative feedback loop in the first place? The article claims long term improvement for the mice, which were genetically programmed for amyloid production. (So maybe not an accurate simulation of the root cause, but perhaps actually more of a steel man test.)
perdomon 11mo ago
This scandal comes to mind any time I see amyloid plaque research. Not sure if I misunderstood the scandal or if Alzheimer’s research has too much momentum to pivot. My dad was diagnosed a few years back and seeing stuff like this is always encouraging and infuriating because of this science article.
bpodgursky 11mo ago
Fraudulent research should be treated as no-info, not a negative signal on the target. You can have fraudulent research supporting a correct theory. In fact this is more common, people will generally fake evidence to support a theory they think is probably true.

by chc4 11mo ago

epgui 11mo ago

Yes, in a sense... but that doesn't mean amyloid-beta is an irrelevant therapeutic target. It's a bit more complicated.

jvanderbot 11mo ago

IIRC, it was revealed that treating this as a cause is wrong, it complicates or causes dementia, but is a symptom of something else, not a root cause of the disease. But treating symptoms, esp restoring cognitive function, is a good thing.

p_j_w 11mo ago

I'm not a neuroscientist, but it seems that hypothesis existed before that paper and has more supporting evidence than what's been retracted: https://en.wikipedia.org/wiki/Biochemistry_of_Alzheimer%27s_disease#Amyloid_hypothesis https://en.wikipedia.org/wiki/Biochemistry_of_Alzheimer%27s_...

mjamesaustin 11mo ago

This therapy doesn't target the amyloid-beta plaques. It repairs the blood brain barrier, and then the body is able to clear away the plaques. Their buildup is a symptom of Alzheimers, not the cause. The problem with the amyloid-beta hypothesis was the assumption that these plaques were causing the Alzheimers and that removing them by itself could lead to a cure.

lukeinator42 11mo ago
Exactly this. Amyloid-beta plaques and their association with dementia were discovered early on (late 1800s/early 1900s https://en.wikipedia.org/wiki/Amyloid_plaques#History https://en.wikipedia.org/wiki/Amyloid_plaques#History), but the theory that they cause dementia hasn't panned out.
matthewdgreen 11mo ago
Whoa there. Is that what’s happening? Cause an alternative theory is cause -> plaques -> cognitive disease. You seem to be arguing cause -> cognitive disease -> plaques, and I’m not sure this research demonstrates that. Does it?
- celrod 11mo ago
  I think they're arguing Cause -> cognitive disease Cause -> plaques That is, that the same cause is behind both. There may be some arrows from plaque to disease as well (i.e., that plaques also increase disease). I dont know the truth, but just trying to understand/follow Alzheimers news and reading comments.
- pessimizer 11mo ago
  Why does it seem like they're arguing that? I think that it's supposed to really be: cause -> (plaques = cognitive disease), and the fraud was (cause = plaques) -> cognitive disease. As I took it, understanding that there was a fraud doesn't mean that continually clearing the plaques wouldn't have a good chance of holding off cognitive disease indefinitely.
  - matthewdgreen 11mo ago
    I'm simply arguing that the plaques could be the proximate cause and the problem addressed by this treatment could be the remote cause. The OP is being vague in the way they stated it, but it feels like they're saying the plaques are irrelevant. That doesn't seem to fit what we know: the evidence that cognitive symptoms are downstream of plaques is pretty compelling. I also don't think "fraud" should be used in this discussion at all. With all that said, if this One Weird Trick can clear/prevent the buildup of plaques (and thus the cognitive symptoms downstream of them), that's just a best possible outcome.

shawnz 11mo ago

Here's a good article which explains the remaining arguments in favour of the amyloid hypothesis: https://www.astralcodexten.com/p/in-defense-of-the-amyloid-hypothesis https://www.astralcodexten.com/p/in-defense-of-the-amyloid-h...

amalcon 11mo ago

It's most likely highly correlated, but not causative. That correlation still makes it diagnostically useful, which is how it's used here.

tremon 11mo ago
I thought amyloid-β buildup is usually determined at autopsy? That's not really the kind of diagnostic medicine I'm looking forward to. Can it also be determined via brain biopsy?
- mattkrause 11mo ago
  You can do PET imaging for it--there are a bunch of 18F-based tracers that work reasonably well. It also inversely correlates with Abeta levels in the CSF. Ne Neither of those are particularly easy procedures, but certainly better than a biopsy (and autopsy!) https://pmc.ncbi.nlm.nih.gov/articles/PMC3264790/ https://pmc.ncbi.nlm.nih.gov/articles/PMC3264790/
JamesBarney 11mo ago
It's very likely causative. There is just too much evidence for it not to be. All the genes related to amyloid processing are correlated with Alzheimer rates. The most likely theory I've seen is amyloid causes tau buildup which leads to the majority of the damage. And by the time they give anti-amyloid drugs it's too late and the tau is doing the majority of the damage. An analogy would be if you have a hole in your house which leads to getting a rat infestation. Once you notice the rat infestation patching the hole isn't going to solve your problem. The hole caused you to get rat shit on your counter, but by the time you fix the hole it's too late to stop the rats from shitting on your counter.

bitshiftfaced 11mo ago

This article: https://www.astralcodexten.com/p/in-defense-of-the-amyloid-hypothesis https://www.astralcodexten.com/p/in-defense-of-the-amyloid-h... makes a pretty compelling argument for continued research on the link between amyloid-beta and Alzheimer's.

matthewdgreen 11mo ago
This article is incredibly informative and I wish the folks in this thread would read it. Doesn’t make the current result any less exciting.
dcrazy 11mo ago
Not saying it’s wrong or worthless, but do keep in mind that neither the author not the blog owner is in the medical field. That post is an outsider’s read of the consensus opinion from their investigation of the literature, including an estimate of the strength of that literature formed without expertise in the field itself.
- larsiusprime 11mo ago
  Scott Alexander is in fact an MD

JamesBarney 11mo ago

There were some important papers that turned out to be fraudulent, but there is a large and broad body of knowledge supporting this link.

JoshTriplett 11mo ago

It's correlated, much as body temperature is correlated with infection. But much like lowering body temperature won't cure the infection, directly addressing the amyloid-beta plaques doesn't seem likely to directly address Alzhimer's. Addressing the actual root cause may also make the plaques go away.

anon84873628 11mo ago
FWIW the article says this: >"The long-term effect comes from restoring the brain’s vasculature. We think it works like a cascade: when toxic species such as amyloid-beta (Aβ) accumulate, disease progresses. But once the vasculature is able to function again, it starts clearing Aβ and other harmful molecules, allowing the whole system to recover its balance. What’s remarkable is that our nanoparticles act as a drug and seem to activate a feedback mechanism that brings this clearance pathway back to normal levels,” >... >Normally, the protein LRP1 acts as a molecular gatekeeper, binding to Aβ and transporting it across the BBB for elimination. In Alzheimer’s, this system becomes fragile, leading to Aβ accumulation. The supramolecular drugs mimic LRP1 ligands, binding to Aβ and initiating its clearance, effectively resetting the system and restoring vascular function. So we may be lucky in that addressing the plaques as a symptom does indeed (allow for) repair of the underlying cause. I guess the question is how long the benefit lasts. What triggers the negative feedback loop in the first place? The article claims long term improvement for the mice, which were genetically programmed for amyloid production. (So maybe not an accurate simulation of the root cause, but perhaps actually more of a steel man test.)

perdomon 11mo ago

This scandal comes to mind any time I see amyloid plaque research. Not sure if I misunderstood the scandal or if Alzheimer’s research has too much momentum to pivot. My dad was diagnosed a few years back and seeing stuff like this is always encouraging and infuriating because of this science article.

bpodgursky 11mo ago

Fraudulent research should be treated as no-info, not a negative signal on the target. You can have fraudulent research supporting a correct theory. In fact this is more common, people will generally fake evidence to support a theory they think is probably true.