7 ms·

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

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-antibodies-alzheimer-you-already-know https://www.science.org/content/blog-post/anti-amyloid-antib...

bluGill 4mo ago
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.
- vlovich123 4mo ago
  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 4mo ago
    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 4mo ago
      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 4mo ago
      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.
- TaupeRanger 4mo ago
  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 4mo ago
    > 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 4mo ago
      https://pubs.acs.org/doi/10.1021/acschemneuro.6c00252 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 4mo ago
        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 4mo ago
- aBioGuy 4mo ago
  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 4mo ago
  > 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.
dbcurtis 4mo ago
> 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 4mo ago
  Yes. And to anyone paying attention, this has been current since about 2010.
  - whatisthiseven 4mo ago
    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 4mo ago
  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.
  - bijowo1676 4mo ago
    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-alzheimers-plaques-may-be-protective-not-destructive/ https://www.salk.edu/news-release/in-surprising-twist-some-a...
  - armadsen 4mo ago
gwbas1c 4mo ago
The podcast "Why Has There Been So Little Progress on Alzheimer’s Disease?" https://freakonomics.com/podcast/why-has-there-been-so-little-progress-on-alzheimers-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.
cassepipe 4mo ago
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)
pfdietz 4mo ago
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.
yxhuvud 4mo ago
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.

bluGill 4mo ago

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.

vlovich123 4mo ago
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 4mo ago
  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 4mo ago
    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 4mo ago
    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.
TaupeRanger 4mo ago
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 4mo ago
  > 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 4mo ago
    https://pubs.acs.org/doi/10.1021/acschemneuro.6c00252 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 4mo ago
      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 4mo ago
aBioGuy 4mo ago
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 4mo ago
> 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.

dbcurtis 4mo ago

> 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 4mo ago
Yes. And to anyone paying attention, this has been current since about 2010.
- whatisthiseven 4mo ago
  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 4mo ago
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.
- bijowo1676 4mo ago
  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-alzheimers-plaques-may-be-protective-not-destructive/ https://www.salk.edu/news-release/in-surprising-twist-some-a...
- armadsen 4mo ago

gwbas1c 4mo ago

The podcast "Why Has There Been So Little Progress on Alzheimer’s Disease?" https://freakonomics.com/podcast/why-has-there-been-so-little-progress-on-alzheimers-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.

cassepipe 4mo ago

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)

pfdietz 4mo ago

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.

yxhuvud 4mo ago

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.