3 ms·

>"Just don't lose sight of the fact that the amyloid hypothesis did and still does have good evidence for it." What is this evidence? The evidence I know of is

by nonbel 8y ago

>"Just don't lose sight of the fact that the amyloid hypothesis did and still does have good evidence for it." What is this evidence? The evidence I know of is quite weak. There are a few correlations here and there, and the "amyloid hypothesis" has never even yielded some kind of quantitative model to be tested. Instead it just keeps getting more and more byzantine".

db48x 8y ago
Yea, the evidence for it was never amazing, in absolute terms. But how much of that is hindsight? The alternative theories have even worse evidence, so the evidence for it was obviously good enough to convince a large number of people to spend a decade or more on it. If you think that the evidence was so weak that everybody who worked on it is crazy, then you're wrong. It'll take years of work before anyone has an alternative theory with as much going for it.
- nonbel 8y ago
  >"But how much of that is hindsight?" I can't say personally. As commented elsewhere, I first looked into it about 2014 and almost immediately thought this amyloid hypothesis should have died years ago. >"the evidence for it was obviously good enough to convince a large number of people to spend a decade or more on it" This doesnt mean much to me. If thats where the funding is then people will link their research to it. If NIH is about "aging" this year then you change your grant to use "aged rats", or somehow link your study to "climate change" or whatever. >"If you think that the evidence was so weak that everybody who worked on it is crazy, then you're wrong." Crazy, no. Personally, I think it was a near total lack of quantitative thought. Stuff like people teaching/learning "APP and presenilin mutations are linked to Alzheimers", when it was only single digit or less percent of cases that could account for: >"The first mutation causing the familial form of the disease was identified in the amyloid precursor protein (APP) gene on chromosome 21.8 When investigating other families with the familial disease, several additional APP mutations were found. However, these mutations explain only a few familial cases. Instead, mutations in the highly homologous presenilin 1 (PSEN1) and presenilin 2 (PSEN2) genes account for most cases of familial disease.9,10 However, the familial form of the disease is rare, with a prevalence below 0·1%.11" https://www.ncbi.nlm.nih.gov/pubmed/16876668 https://www.ncbi.nlm.nih.gov/pubmed/16876668
  - db48x 8y ago
    >> the evidence for it was obviously good enough to convince a large number of people to spend a decade or more on it > This doesnt mean much to me. If thats where the funding is then people will link their research to it. If NIH is about "aging" this year then you change your grant to use "aged rats", or somehow link your study to "climate change" or whatever. I don't mean doing research with grant money, I mean that hundreds of people at half a dozen or more companies spent billions of dollars of private funding and at least a decade of their lives to develop drugs based on the amyloid hypothesis. That means that the evidence was good enough, or the evidence for any alternatives bad enough, to speculate on. Drug development is always speculative, but it's not crazy or irrational. And it's not a lack of quantitative thought, either; it's speculation. But my purpose here wasn't to defend the evidence (as you seem to want me to do), it was merely to point out that for all this time "the" amyloid hypothesis (again, it's a family of hypotheses because each drug has a different intended mechanism of action and is therefore a different testable hypothesis) has been the only workable theory of how the disease works. Thus someone used the word "unthinkable", which you objected to. He clearly didn't mean it literally, since people have actually thought about alternatives, so it must have been hyperbole. Since he probably agrees with you that the evidence is weak in absolute terms, I don't see why you would object to the hyperbole. I pointed it out because your question (which was "What made it so previously unthinkable?") indicated that you were taking the word literally.
    - nonbel 8y ago
      >'"the" amyloid hypothesis (again, it's a family of hypotheses because each drug has a different intended mechanism of action and is therefore a different testable hypothesis) has been the only workable theory of how the disease works.' Afaict, there was nothing especially workable about it vs eg the "cholinergic hypothesis". In fact the only drugs that are said to help were devised based on that hypothesis.[1] So something else is going on here. [1] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3956752/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3956752/

by nonbel 8y ago

db48x 8y ago

Yea, the evidence for it was never amazing, in absolute terms. But how much of that is hindsight? The alternative theories have even worse evidence, so the evidence for it was obviously good enough to convince a large number of people to spend a decade or more on it. If you think that the evidence was so weak that everybody who worked on it is crazy, then you're wrong. It'll take years of work before anyone has an alternative theory with as much going for it.

nonbel 8y ago
>"But how much of that is hindsight?" I can't say personally. As commented elsewhere, I first looked into it about 2014 and almost immediately thought this amyloid hypothesis should have died years ago. >"the evidence for it was obviously good enough to convince a large number of people to spend a decade or more on it" This doesnt mean much to me. If thats where the funding is then people will link their research to it. If NIH is about "aging" this year then you change your grant to use "aged rats", or somehow link your study to "climate change" or whatever. >"If you think that the evidence was so weak that everybody who worked on it is crazy, then you're wrong." Crazy, no. Personally, I think it was a near total lack of quantitative thought. Stuff like people teaching/learning "APP and presenilin mutations are linked to Alzheimers", when it was only single digit or less percent of cases that could account for: >"The first mutation causing the familial form of the disease was identified in the amyloid precursor protein (APP) gene on chromosome 21.8 When investigating other families with the familial disease, several additional APP mutations were found. However, these mutations explain only a few familial cases. Instead, mutations in the highly homologous presenilin 1 (PSEN1) and presenilin 2 (PSEN2) genes account for most cases of familial disease.9,10 However, the familial form of the disease is rare, with a prevalence below 0·1%.11" https://www.ncbi.nlm.nih.gov/pubmed/16876668 https://www.ncbi.nlm.nih.gov/pubmed/16876668
- db48x 8y ago
  >> the evidence for it was obviously good enough to convince a large number of people to spend a decade or more on it > This doesnt mean much to me. If thats where the funding is then people will link their research to it. If NIH is about "aging" this year then you change your grant to use "aged rats", or somehow link your study to "climate change" or whatever. I don't mean doing research with grant money, I mean that hundreds of people at half a dozen or more companies spent billions of dollars of private funding and at least a decade of their lives to develop drugs based on the amyloid hypothesis. That means that the evidence was good enough, or the evidence for any alternatives bad enough, to speculate on. Drug development is always speculative, but it's not crazy or irrational. And it's not a lack of quantitative thought, either; it's speculation. But my purpose here wasn't to defend the evidence (as you seem to want me to do), it was merely to point out that for all this time "the" amyloid hypothesis (again, it's a family of hypotheses because each drug has a different intended mechanism of action and is therefore a different testable hypothesis) has been the only workable theory of how the disease works. Thus someone used the word "unthinkable", which you objected to. He clearly didn't mean it literally, since people have actually thought about alternatives, so it must have been hyperbole. Since he probably agrees with you that the evidence is weak in absolute terms, I don't see why you would object to the hyperbole. I pointed it out because your question (which was "What made it so previously unthinkable?") indicated that you were taking the word literally.
  - nonbel 8y ago
    >'"the" amyloid hypothesis (again, it's a family of hypotheses because each drug has a different intended mechanism of action and is therefore a different testable hypothesis) has been the only workable theory of how the disease works.' Afaict, there was nothing especially workable about it vs eg the "cholinergic hypothesis". In fact the only drugs that are said to help were devised based on that hypothesis.[1] So something else is going on here. [1] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3956752/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3956752/