5 ms·

Hasn’t the entire amyloid theory been coming under a huge amount of scrutiny recently for being almost a mafia-like cabal of somewhat questionable science?

ncmncm 4y ago
Certainly about every paper nowadays is about stuff going on in a breed of mice engineered to produce lots of amyloid plaques. Hardly nobody knows or cares what happens in actual patients. The best methods we know of to protect real people against dementia are: 1. Get vaccinations. It doesn't seem to matter so much which ones. But Tdap and flu are seen to do the job. 2. Eat plenty of cheese. 3. Get treatment for herpes. I think valacyclovir is the mainstay. 4. Keep your gums healthy. There is no rigorous information to indicate why these seem to make a difference. Precious few people are looking. Certainly the people in charge of grants for Alzheimer's research are not awarding them for any such effort. When the whole house of amyloid cards finally collapses, what will amyloid specialists do with the rest of their careers? Maybe it would be smart to get a jump on that now...
- bilsbie 4y ago
  How much of that is the healthy user bias though. Those are all things healthy people generally do.
  - macrolime 4y ago
    Healthy people generally eats lots of cheese and valacyclovir?
    - jrussino 4y ago
      You don't serve Emmenthaltrex at your cocktail parties? ;-)
    - ncmncm 4y ago
      "If you think of the vastness of space, and how enormous our galaxy is, and how big our planet is, and how small we are, I am not really eating all that much cheese."
- UncleOxidant 4y ago
  Cheese? Where is that coming from?
  - mmastrac 4y ago
    Most studies are done on mice... /s But seriously, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6073537/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6073537/ > Oleamide and dehydroergosterol identified from Camembert cheese induce microglia into the M2 anti-inflammatory phenotype, leading to neuroprotection. The mechanisms that regulate microglial activation and inflammation in Alzheimer’s disease are important targets for disease prevention. The regulation of microglia via daily lifestyle habits has been receiving increasing attention. The intake of neuroprotective and anti-inflammatory compounds including oleamide and dehydroergosterol in meals is safe and easy, so nutritional approaches are promising for the prevention of neurodegenerative disorders.
    - AlbertCory 4y ago
      Camembert, the new SuperFood! Now there's some news I can use.
    - ekianjo 4y ago
      mice models are almost never applicable to humans... and I have a very hard time believing that simple foods play a major role in protection.
      - ncmncm 4y ago
        Population studies seem to support it. Not just camembert, of course.
        ekianjo 4y ago
        population studies are very hard to control for and most of the data is purely self reported which is close to junk level
- canadiantim 4y ago
  Where are you getting your information on the methods to protect against dementia? That seems like a very dubious list tbh
  - ncmncm 4y ago
    This is mostly from well-run population studies. The effect sizes are very large and robust, e.g. 40% for Tdap. Herpes treatment, from a small RCT in Asia. Hypothesis is that amyloids are a response to inflammation, and things that reduce inflammation (including blocking various infections) help. But nobody knows, really. Or is trying very hard to find out. It would be criminal negligence, except it is all perfectly legal, like most corruption in the US. Grant money for Alzheimer's research ($2B/y?) is controlled by people who have made a career of chasing ways to suppress amyloid production. They are not about to waste any on people they don't know wandering unlikely blind alleys when ways to suppress amyloid production (in these mice) are not fully explored. They divert some for tau tangles, and how much good has come of that?
JamesBarney 4y ago
This is an exaggeration for clicks. We've since discovered that amyloid beta is probably not the cause. At least isn't very casual, or has sophisticated causality by the time we start treating people. It's also true there were people in control of Alzheimer's spending who had blinders on. But! There was a lot of reasons to think it was amyloid-beta, everyone with Alzheimer's has amyloid beta, early onset Alzheimer's is related to amyloid beta processing, mice that produce lots of amyloid beta or are injected with amyloid beta have Alzheimer's like symptoms.
- AlbertCory 4y ago
  I don't think I would call it clickbait. As you said, "there were people in control of Alzheimer's spending who had blinders on." If something sounds good (as everyone admits) but it's failed over and over, and certain people with power shut down any alternatives, then "mafia" is maybe pejorative but not unfair.
  - MaxfordAndSons 4y ago
    I think "cartel" rather than "mafia" would be the more apt pejorative.
    - AlbertCory 4y ago
      I'll go with that.
jcranmer 4y ago
> Hasn’t the entire amyloid theory been coming under a huge amount of scrutiny Yes. > recently I'm using Derek Lowe as my litmus test for how the field reacts, and he's been leaning against it since around 2015-ish. So "recently" might not be all that recent. > for being almost a mafia-like cabal of somewhat questionable science? Uh, what? It recently came out that one of the papers in Alzheimer's research was faked. However, the importance of that faking on the field is actually relatively little: what it purported to establish was a direct causative link between a single amyloid precursor and memory decline--which was already the prevailing theory. As Derek Lowe describes it (https://www.science.org/content/blog-post/faked-beta-amyloid-data-what-does-it-mean https://www.science.org/content/blog-post/faked-beta-amyloid...): > I could be wrong about this, but from this vantage point the original Lesné paper and its numerous follow-ups have largely just given people in the field something to point at when asked about the evidence for amyloid oligomers directly affecting memory. I’m not sure how many groups tried to replicate the findings, although (as just mentioned) when people did it looks like they indeed couldn’t find the 56 oligomer. And judging from the number of faked Westerns, that’s probably because it doesn’t exist in the first place. 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. In other words, amyloid hypothesis was prevailing before the paper anyways, it would have remained prevailing without the paper, and the paper itself never appears to have directly inspired actual clinical work on any of the failing drugs. It's hard to believe that the field would have abandoned amyloid hypothesis without the failure: there are many other reasons to believe the amyloid hypothesis, and the main reason to not believe it is only because clearing amyloid hasn't improved Alzheimer's in actual drug candidates*.
zosima 4y ago
There is a huge amount of genetic evidence that amyloid-beta or its precursor APP is involved and causal in Alzheimer's. That's not in question. But since there's been so many trial failures trying to get rid of amyloid-beta, it has become clear that there's something missing to the story. I think talking of mafia or cabals is a bit exaggerated, but perhaps there has been a bit too much focus on the easy-to-see and study plaques and aggregates of amyloid-beta and to little on what happens before the plaques develop. (Something that is much harder)

ncmncm 4y ago

Certainly about every paper nowadays is about stuff going on in a breed of mice engineered to produce lots of amyloid plaques. Hardly nobody knows or cares what happens in actual patients. The best methods we know of to protect real people against dementia are: 1. Get vaccinations. It doesn't seem to matter so much which ones. But Tdap and flu are seen to do the job. 2. Eat plenty of cheese. 3. Get treatment for herpes. I think valacyclovir is the mainstay. 4. Keep your gums healthy. There is no rigorous information to indicate why these seem to make a difference. Precious few people are looking. Certainly the people in charge of grants for Alzheimer's research are not awarding them for any such effort. When the whole house of amyloid cards finally collapses, what will amyloid specialists do with the rest of their careers? Maybe it would be smart to get a jump on that now...

bilsbie 4y ago
How much of that is the healthy user bias though. Those are all things healthy people generally do.
- macrolime 4y ago
  Healthy people generally eats lots of cheese and valacyclovir?
  - jrussino 4y ago
    You don't serve Emmenthaltrex at your cocktail parties? ;-)
  - ncmncm 4y ago
    "If you think of the vastness of space, and how enormous our galaxy is, and how big our planet is, and how small we are, I am not really eating all that much cheese."
UncleOxidant 4y ago
Cheese? Where is that coming from?
- mmastrac 4y ago
  Most studies are done on mice... /s But seriously, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6073537/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6073537/ > Oleamide and dehydroergosterol identified from Camembert cheese induce microglia into the M2 anti-inflammatory phenotype, leading to neuroprotection. The mechanisms that regulate microglial activation and inflammation in Alzheimer’s disease are important targets for disease prevention. The regulation of microglia via daily lifestyle habits has been receiving increasing attention. The intake of neuroprotective and anti-inflammatory compounds including oleamide and dehydroergosterol in meals is safe and easy, so nutritional approaches are promising for the prevention of neurodegenerative disorders.
  - AlbertCory 4y ago
    Camembert, the new SuperFood! Now there's some news I can use.
  - ekianjo 4y ago
    mice models are almost never applicable to humans... and I have a very hard time believing that simple foods play a major role in protection.
    - ncmncm 4y ago
      Population studies seem to support it. Not just camembert, of course.
      - ekianjo 4y ago
        population studies are very hard to control for and most of the data is purely self reported which is close to junk level
canadiantim 4y ago
Where are you getting your information on the methods to protect against dementia? That seems like a very dubious list tbh
- ncmncm 4y ago
  This is mostly from well-run population studies. The effect sizes are very large and robust, e.g. 40% for Tdap. Herpes treatment, from a small RCT in Asia. Hypothesis is that amyloids are a response to inflammation, and things that reduce inflammation (including blocking various infections) help. But nobody knows, really. Or is trying very hard to find out. It would be criminal negligence, except it is all perfectly legal, like most corruption in the US. Grant money for Alzheimer's research ($2B/y?) is controlled by people who have made a career of chasing ways to suppress amyloid production. They are not about to waste any on people they don't know wandering unlikely blind alleys when ways to suppress amyloid production (in these mice) are not fully explored. They divert some for tau tangles, and how much good has come of that?

JamesBarney 4y ago

This is an exaggeration for clicks. We've since discovered that amyloid beta is probably not the cause. At least isn't very casual, or has sophisticated causality by the time we start treating people. It's also true there were people in control of Alzheimer's spending who had blinders on. But! There was a lot of reasons to think it was amyloid-beta, everyone with Alzheimer's has amyloid beta, early onset Alzheimer's is related to amyloid beta processing, mice that produce lots of amyloid beta or are injected with amyloid beta have Alzheimer's like symptoms.

AlbertCory 4y ago
I don't think I would call it clickbait. As you said, "there were people in control of Alzheimer's spending who had blinders on." If something sounds good (as everyone admits) but it's failed over and over, and certain people with power shut down any alternatives, then "mafia" is maybe pejorative but not unfair.
- MaxfordAndSons 4y ago
  I think "cartel" rather than "mafia" would be the more apt pejorative.
  - AlbertCory 4y ago
    I'll go with that.

jcranmer 4y ago

> Hasn’t the entire amyloid theory been coming under a huge amount of scrutiny Yes. > recently I'm using Derek Lowe as my litmus test for how the field reacts, and he's been leaning against it since around 2015-ish. So "recently" might not be all that recent. > for being almost a mafia-like cabal of somewhat questionable science? Uh, what? It recently came out that one of the papers in Alzheimer's research was faked. However, the importance of that faking on the field is actually relatively little: what it purported to establish was a direct causative link between a single amyloid precursor and memory decline--which was already the prevailing theory. As Derek Lowe describes it (https://www.science.org/content/blog-post/faked-beta-amyloid-data-what-does-it-mean https://www.science.org/content/blog-post/faked-beta-amyloid...): > I could be wrong about this, but from this vantage point the original Lesné paper and its numerous follow-ups have largely just given people in the field something to point at when asked about the evidence for amyloid oligomers directly affecting memory. I’m not sure how many groups tried to replicate the findings, although (as just mentioned) when people did it looks like they indeed couldn’t find the 56 oligomer. And judging from the number of faked Westerns, that’s probably because it doesn’t exist in the first place. 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. In other words, amyloid hypothesis was prevailing before the paper anyways, it would have remained prevailing without the paper, and the paper itself never appears to have directly inspired actual clinical work on any of the failing drugs. It's hard to believe that the field would have abandoned amyloid hypothesis without the failure: there are many other reasons to believe the amyloid hypothesis, and the main reason to not believe it is only because clearing amyloid hasn't improved Alzheimer's in actual drug candidates*.

zosima 4y ago

There is a huge amount of genetic evidence that amyloid-beta or its precursor APP is involved and causal in Alzheimer's. That's not in question. But since there's been so many trial failures trying to get rid of amyloid-beta, it has become clear that there's something missing to the story. I think talking of mafia or cabals is a bit exaggerated, but perhaps there has been a bit too much focus on the easy-to-see and study plaques and aggregates of amyloid-beta and to little on what happens before the plaques develop. (Something that is much harder)