6 ms·

> Problem was, the model was wrong. I thought despite the fraud, it's still the best model we have[1]? The fact there was fraud doesn't mean the model is immed

by gruez 6mo ago

> Problem was, the model was wrong. I thought despite the fraud, it's still the best model we have[1]? The fact there was fraud doesn't mean the model is immediately incorrect. At best, it means its foundations are shakier than we thought, but it's not a slam dunk repudiation. [1] https://www.astralcodexten.com/p/in-defense-of-the-amyloid-hypothesis https://www.astralcodexten.com/p/in-defense-of-the-amyloid-h...

mnode 6mo ago
Many in the research community realised the model was wrong a long time ago. This is a great read about the reasons why: 'How not to study a disease: the story of Alzheimer’s.' by Karl Herrup.
- ACCount37 6mo ago
  Wrong or incomplete? The current findings seem consistent with "both plaques and tangles are significant components of the pathology" and "our interventions are typically late and the accumulated neurological damage is already extreme by the time clinical symptoms show". Attacking the plaques wasn't completely worthless - findings show that this often slows disease progression, especially in early cases. There are pre-symptomatic trials ongoing that may clear the air on whether "intervention is late" is the main culprit in treatment underperformance.
- sien 6mo ago
  Thanks for recommending this book. I'm now about half way through. It's really good.
Drupon 6mo ago
>I am David Schneider-Joseph, an engineer formerly with SpaceX and Google, now working in AI safety. Alzheimer’s isn’t my field If anyone wants to know who wrote the article linked before wasting time reading it, there you go.
- trhway 6mo ago
  there is even easier way to estimate the chances of time wasting - it is a "rationalist" website, an "effective altruism"-like version of rationality. wrt. original post - quickly googled, and that for example https://www.news-medical.net/health/What-are-Amyloid-Plaques.aspx https://www.news-medical.net/health/What-are-Amyloid-Plaques... - pretty short and seems to be clear that amyloids do have some correlation while may or may be not the cause. "Amyloid plaques form one of the two defining features of Alzheimer’s disease, the other being neurofibrillary tangles" Interesting that the latter is inside the neurons while the former is outside - speaking of complexity. The article also describes that activating microglia back helps with amyloid plaques while this https://pubmed.ncbi.nlm.nih.gov/33010092/#:~:text=The%20study%20found%20that:%20*%20**Ramified%20microglia,contribute%20to%20focal%20neurodegeneration%20characteristic%20of%20PPA%2DAD. https://pubmed.ncbi.nlm.nih.gov/33010092/#:~:text=The%20stud... "The neurofibrillary tangles (NFT) and amyloid-ß plaques (AP) that comprise Alzheimer's disease (AD) neuropathology are associated with neurodegeneration and microglial activation. " Human body reminds a large monolith codebase - fixing one thing breaks some other :). Claude Code, Human Body CRISPR edition, can't come soon enough...
  - ifwinterco 6mo ago
    Huge codebase with years of fixes, features and hacks added on top and nothing ever refactored. It’s a miracle it works at all
    - generic92034 6mo ago
      It is worse. The code changes are mostly random, only surviving the tests of fitness nature is applying (on various levels though; immediately catastrophic changes on level of cell biology are sorted out). And at least the high-level tests are also random and unreliable.
      - ravenstine 6mo ago
        So basically it's a codebase mostly composed of bugs, and the features mysteriously work because they're based on bugs that happen to be mitigated by other bugs. :)
friendzis 6mo ago
It's a classic example of "correlation does not imply causation". It was indeed observed that some patients with neurodegenerative conditions do indeed have amyloid plaques. It was further observed that patients with known Alzheimer's do not necessarily have amyloid plaques and patients without it do have plaques. The existence of amyloid plaques itself or the level, apparently, correlates extremely poorly, if at all, with the existence, onset or severity of the disease. Drugs attacking amyloid plaques might work, but they don't reverse the disease and do very little to slow progression. That's all scientific observations. > I thought despite the fraud, it's still the best model we have[1]? It is observed that one of the features of neurodegenerative diseases is decline in glucose metabolism. Supplementing energy availability (e.g. ketones [1], creatine [2]) does improve symptoms in patients with wide variety of CNS diseases, including Alzheimer's, senile dementia, epilepsy, and migraines. The ATN model you have linked might as well be just ONE OF possible pathways to glucose uptake inhibition, which could be the causal pathology of the symptoms. So no, it is very much not necessarily the best model we have. Inhibiting any pathway towards a disease is always a good thing, but the characteristics of "best" models are broad applicability and we have a serious contender. [1]: https://link.springer.com/article/10.1016/j.nurt.2008.05.004 https://link.springer.com/article/10.1016/j.nurt.2008.05.004 [2]: https://alz-journals.onlinelibrary.wiley.com/doi/full/10.1002/trc2.70101 https://alz-journals.onlinelibrary.wiley.com/doi/full/10.100...
bradley13 6mo ago
Pretty clearly not. It would seem that beta amyloids correlate with Alzheimer's, but do not cause it. The problem us "consensus science". You could get funding to research beta amyloids, but not to research any competing hypotheses. It's much like climate science today: any dissent at all, even just questioning the predictions of catastrophe, immediately brands you as a heretic.
- enraged_camel 6mo ago
  >> It's much like climate science today: any dissent at all, even just questioning the predictions of catastrophe, immediately brands you as a heretic. Nonsense. It is actually quite unlike climate science, where the consensus of catastrophe and the evidence for it are both overwhelming. Dissenters are listened to only to the extent they can provide overwhelming evidence to the contrary, which they so far cannot.
- stingraycharles 6mo ago
  > It's much like climate science today: any dissent at all, even just questioning the predictions of catastrophe, immediately brands you as a heretic. I think this is not a great example, as there’s a huge group of people that, in fact, does not agree with the consensus and would happily fund research that (tries to) prove otherwise. I fully agree with your point, though, just not the example.
  - defrost 6mo ago
    Over the past decades the group that are not happy with the AGW consensus in the hard earth sciences crowd have principally funded FUD via think tanks, ala the pro-tobacco lobby back in the day, rather than research. The few examples of research driven from the skeptic PoV (eg: urban heat skewing, etc) have landed on the side of the AGW consensus.
    - TheOtherHobbes 6mo ago
      And when they funded research, it confirmed the known science. https://www.scientificamerican.com/article/exxon-knew-about-climate-change-almost-40-years-ago/ https://www.scientificamerican.com/article/exxon-knew-about-... If anything the current consensus on the scientific front lines is that the alarmism is understated, and the real orthodoxy is astroturfed denial of the facts. The global fossil industry is worth around $11 trillion a year. It supports some of the worst regimes in the world. Of course they're going to try to FUD away the science, with the usual copy-paste narratives about how it's really scientists and academics who are corrupt. It's all about money, power, and entitlement. Not about truth or responsibility. But no amount of PR nonsense, astroturfing, and false accusation is going to make the slightest difference to climate reality.
caycep 6mo ago
the model is wrong, but the amyloid is still sitting there, staring at you, asking you what are you going to do about it?

by gruez 6mo ago

mnode 6mo ago

Many in the research community realised the model was wrong a long time ago. This is a great read about the reasons why: 'How not to study a disease: the story of Alzheimer’s.' by Karl Herrup.

ACCount37 6mo ago
Wrong or incomplete? The current findings seem consistent with "both plaques and tangles are significant components of the pathology" and "our interventions are typically late and the accumulated neurological damage is already extreme by the time clinical symptoms show". Attacking the plaques wasn't completely worthless - findings show that this often slows disease progression, especially in early cases. There are pre-symptomatic trials ongoing that may clear the air on whether "intervention is late" is the main culprit in treatment underperformance.
sien 6mo ago
Thanks for recommending this book. I'm now about half way through. It's really good.

Drupon 6mo ago

>I am David Schneider-Joseph, an engineer formerly with SpaceX and Google, now working in AI safety. Alzheimer’s isn’t my field If anyone wants to know who wrote the article linked before wasting time reading it, there you go.

trhway 6mo ago
there is even easier way to estimate the chances of time wasting - it is a "rationalist" website, an "effective altruism"-like version of rationality. wrt. original post - quickly googled, and that for example https://www.news-medical.net/health/What-are-Amyloid-Plaques.aspx https://www.news-medical.net/health/What-are-Amyloid-Plaques... - pretty short and seems to be clear that amyloids do have some correlation while may or may be not the cause. "Amyloid plaques form one of the two defining features of Alzheimer’s disease, the other being neurofibrillary tangles" Interesting that the latter is inside the neurons while the former is outside - speaking of complexity. The article also describes that activating microglia back helps with amyloid plaques while this https://pubmed.ncbi.nlm.nih.gov/33010092/#:~:text=The%20study%20found%20that:%20*%20**Ramified%20microglia,contribute%20to%20focal%20neurodegeneration%20characteristic%20of%20PPA%2DAD. https://pubmed.ncbi.nlm.nih.gov/33010092/#:~:text=The%20stud... "The neurofibrillary tangles (NFT) and amyloid-ß plaques (AP) that comprise Alzheimer's disease (AD) neuropathology are associated with neurodegeneration and microglial activation. " Human body reminds a large monolith codebase - fixing one thing breaks some other :). Claude Code, Human Body CRISPR edition, can't come soon enough...
- ifwinterco 6mo ago
  Huge codebase with years of fixes, features and hacks added on top and nothing ever refactored. It’s a miracle it works at all
  - generic92034 6mo ago
    It is worse. The code changes are mostly random, only surviving the tests of fitness nature is applying (on various levels though; immediately catastrophic changes on level of cell biology are sorted out). And at least the high-level tests are also random and unreliable.
    - ravenstine 6mo ago
      So basically it's a codebase mostly composed of bugs, and the features mysteriously work because they're based on bugs that happen to be mitigated by other bugs. :)

friendzis 6mo ago

It's a classic example of "correlation does not imply causation". It was indeed observed that some patients with neurodegenerative conditions do indeed have amyloid plaques. It was further observed that patients with known Alzheimer's do not necessarily have amyloid plaques and patients without it do have plaques. The existence of amyloid plaques itself or the level, apparently, correlates extremely poorly, if at all, with the existence, onset or severity of the disease. Drugs attacking amyloid plaques might work, but they don't reverse the disease and do very little to slow progression. That's all scientific observations. > I thought despite the fraud, it's still the best model we have[1]? It is observed that one of the features of neurodegenerative diseases is decline in glucose metabolism. Supplementing energy availability (e.g. ketones [1], creatine [2]) does improve symptoms in patients with wide variety of CNS diseases, including Alzheimer's, senile dementia, epilepsy, and migraines. The ATN model you have linked might as well be just ONE OF possible pathways to glucose uptake inhibition, which could be the causal pathology of the symptoms. So no, it is very much not necessarily the best model we have. Inhibiting any pathway towards a disease is always a good thing, but the characteristics of "best" models are broad applicability and we have a serious contender. [1]: https://link.springer.com/article/10.1016/j.nurt.2008.05.004 https://link.springer.com/article/10.1016/j.nurt.2008.05.004 [2]: https://alz-journals.onlinelibrary.wiley.com/doi/full/10.1002/trc2.70101 https://alz-journals.onlinelibrary.wiley.com/doi/full/10.100...

bradley13 6mo ago

Pretty clearly not. It would seem that beta amyloids correlate with Alzheimer's, but do not cause it. The problem us "consensus science". You could get funding to research beta amyloids, but not to research any competing hypotheses. It's much like climate science today: any dissent at all, even just questioning the predictions of catastrophe, immediately brands you as a heretic.

enraged_camel 6mo ago
>> It's much like climate science today: any dissent at all, even just questioning the predictions of catastrophe, immediately brands you as a heretic. Nonsense. It is actually quite unlike climate science, where the consensus of catastrophe and the evidence for it are both overwhelming. Dissenters are listened to only to the extent they can provide overwhelming evidence to the contrary, which they so far cannot.
stingraycharles 6mo ago
> It's much like climate science today: any dissent at all, even just questioning the predictions of catastrophe, immediately brands you as a heretic. I think this is not a great example, as there’s a huge group of people that, in fact, does not agree with the consensus and would happily fund research that (tries to) prove otherwise. I fully agree with your point, though, just not the example.
- defrost 6mo ago
  Over the past decades the group that are not happy with the AGW consensus in the hard earth sciences crowd have principally funded FUD via think tanks, ala the pro-tobacco lobby back in the day, rather than research. The few examples of research driven from the skeptic PoV (eg: urban heat skewing, etc) have landed on the side of the AGW consensus.
  - TheOtherHobbes 6mo ago
    And when they funded research, it confirmed the known science. https://www.scientificamerican.com/article/exxon-knew-about-climate-change-almost-40-years-ago/ https://www.scientificamerican.com/article/exxon-knew-about-... If anything the current consensus on the scientific front lines is that the alarmism is understated, and the real orthodoxy is astroturfed denial of the facts. The global fossil industry is worth around $11 trillion a year. It supports some of the worst regimes in the world. Of course they're going to try to FUD away the science, with the usual copy-paste narratives about how it's really scientists and academics who are corrupt. It's all about money, power, and entitlement. Not about truth or responsibility. But no amount of PR nonsense, astroturfing, and false accusation is going to make the slightest difference to climate reality.

caycep 6mo ago

the model is wrong, but the amyloid is still sitting there, staring at you, asking you what are you going to do about it?