5 ms·

Is your view that amyloid is actually a minority view among researchers? That seems completely wrong based on basically every conference proceeding I've viewed

by DavidSJ 3mo ago

Is your view that amyloid is actually a minority view among researchers? That seems completely wrong based on basically every conference proceeding I've viewed and the volume of papers and citations I've examined. If your view is merely that there is a "camp" of experts that disagrees, then sure, but in that case, I do not think it is honest to frame this as a choice between believing in the authority of a single expert from that camp, vs. the (lack of) authority of me, a non-expert. (I also think your read of the evidence is wrong, but I won't restate the arguments in my article.)

dekhn 3mo ago
My opinion is that amyloid-as-cause moved from a majority to a minority view over the past few years, but it's not yet reflected in the literature (the entire amyloid establishment isn't going to give up its dominant position easily). Also, I didn't say anything about the evidence (I don't have a "read" on the evidence, because I don't read Alz literature). My point is entirely that my priors indicate that Derek is a more reliable reader than you.
- DavidSJ 3mo ago
  You said the camp promoting the amyloid hypothesis has struggled greatly to come up with evidence to support its position. What did you mean by that if not a read of the quality of the evidence? Why do you continue to frame this as a choice between a single cherry-picked expert's opinion, and my own non-expert opinion? Either fairly represent the spectrum of experts' views, or decide based on the actual evidence and arguments.
  - dekhn 3mo ago
    My estimate of the quality of the evidence is based on daily discussions with people who work in that field and reading summary articles in major journals. I typically don't read raw scientific articles directly- those are aimed at people in the field. Instead, my understanding comes from a synthesis of expert opinions weighted by my own priors (based on 30+ years in the field). Derek's opinion is now the prevailing one that I hear from a wide range of researchers. I've seen this happen before, btw- overturning establishment paradigms, especially ones where the underlying etiology is complex- is extremely hard and often takes decades of experimental results.
    - DavidSJ 3mo ago
      What started as an argument to ignore arguments and evidence and instead rely on authority, seems now to have morphed into an argument that we should ignore the authority of the establishment, because of your own personal assessment of the evidence (which you have not yourself read) and your own personal synthesis of conversations you've had with researchers you've personally come into contact with (despite this being apparently unrepresentative of objective measures of typical researcher opinions). Arguing from authority really only takes you so far when it ends up as an appeal to your personal experience. I'd rather you either address the arguments directly, or drop the dubious appeal to authority.
      - djdjkddkkd 3mo ago
        [dead]
      - lmeyerov 3mo ago
        I don't have a horse in this race, but for anyone who has worked in it, "science advances one funeral at a time" comes to mind here
      - novia 3mo ago
        update your priors dude
        DavidSJ 3mo ago
        I did. I started out very skeptical, then got convinced by the quality of the evidence.
    - uxhacker 3mo ago
      Your making an argumentum ad verecundiam which even if you are right means we have to discredit it. It’s poor science to make an argument on authority, if you know the science then you should be quoting the published research and not relying on others so called expertise.
      - 3mo ago
  - echelon 3mo ago
    The amyloid and tau people have had over thirty years with nothing to show for it. It's time for the inflammation / diabetes / infection / metabolic dysfunction / liver dysfunction folks to get more money to test their theories.
- john_strinlai 3mo ago
  >My opinion is that amyloid-as-cause moved from a majority to a minority view over the past few years, but it's not yet reflected in the literature >I don't have a "read" on the evidence, because I don't read Alz literature these two sentences seem contradictory to me. i am not sure how you would keep up on the research (to know it's moved from majority-held to minority-held view), and know that the move is not reflected in the literature, without reading the literature.
  - dekhn 3mo ago
    Most scientists who are not experts in their field don't read the literature for a field directly. Instead, they synthesize their opinions about the field by consulting experts, and weighing various sorts of evidence. In my case, I work in an adjacent field and see presentations from scientists, have casual conversations with them, and read the news articles in major journals. The raw literature for alzheimer's, as well as biomed in general, is not really easily interpretable. It's rife with errors, misleading statements, and intentional obfuscation.
kurthr 3mo ago
Wow, it sure didn't take long to show a complete lack of familiarity in the field. It seems like that's going to be a real weakness with LLMs based on volumes of material that are later discovered to be semi-fraudulent and unmotivated by scientific principals. https://stanforddaily.com/2023/12/31/blockbuster-alzheimers-paper-retracted-by-former-stanford-president-after-a-decade-of-resistance/ https://stanforddaily.com/2023/12/31/blockbuster-alzheimers-...
- DavidSJ 3mo ago
  As noted elsewhere in this thread, which you seem not to have read, I discuss that matter in the article, which you also seem not to have read.
  - deleted 3mo ago
    [deleted]
  - kurthr 3mo ago
    Not only have I read it, I know people mentioned in it. There aren't very many.
    - DavidSJ 3mo ago
      You read the article in which I discuss the matter you say I was unfamiliar with?
      - thechao 3mo ago
        I'm responding to a random comment: I was in molecular biology, but >20 years ago. Your article immediately presents as someone who's acquired reading expertise in a biological/medical subfield. Second, your initial survey presents as a "brittle x": AB is the proximal cause all by itself; but, it can also be the secondary cause from many vectors. Diseases like that are (essentially) impossible to explain to the public. Also, the biological principle function is a standard trope for "good for X in the short run, bad for the person in the long run".
pcrh 3mo ago
I have direct experience of research into Alzheimer's disease, including specifically surrounding the amyloid cascade hypothesis. The strength of the amyloid hypothesis is that it is currently the only way to unify early onset AD that is caused by mutations in APP and presenilin with the pathology of both early and late set AD. The weakness is that experimental mice expressing mutated APP do not get neurodegeneration, despite showing amyloid accumulation and behavioral defects. Mice expressing mutated presenilin in contrast do get both behavioral defects and neurodegeneration, despite showing no accumulation of amyloid. "Perhaps mice are different" is the usual response/excuse. This defense is considerably weaker now, given the very modest benefits of removing amyloid from the human brain, as shown in recent clinical trials. So.... when considered rigorously, the amyloid hypothesis remains to be proven. However, it will always have its supporters until there is an alternate explation for the convergence of mutations in APP and presenilin on precisely that region of APP that generates amyloid.
- DavidSJ 3mo ago
  Those are amyloid-only mice. It's an amyloid+tau disease, with tau the proximate cause of neurodegeneration. Normal mice don't get tau pathology, whereas even healthy human beings do, however it stays localized until the presence of widespread amyloid pathology. Causal intervention on amyloid+tau mice is consistent with causal mediation from longitudinal human neuroimaging data: the amyloid pathology greatly accelerates tau pathology, and then this causes neurodegeneration.
  - pcrh 3mo ago
    I appreciate your comment. However, a straight-forward test of the hypothesis that amyloid is the toxic (etiological) agent in AD fails when tested in mice. One may then ask, what is being remedied in the many, many, studies that claim to successfully target amyloid toxicity in mice? And is this relevant to the processes that occur in AD? Human pathology studies are limited in ability to determine causal agents because they are primarily observational, i.e. they find correlations, show that changes in certain other proteins or processes are associated, such as tau that you mention, inflammation, etc. Or as you mention, show that the pathological hallmarks of AD have a stereotypical order of appearance. However, the only human studies that can demonstrate cause in AD are genetic studies.

by DavidSJ 3mo ago

dekhn 3mo ago

My opinion is that amyloid-as-cause moved from a majority to a minority view over the past few years, but it's not yet reflected in the literature (the entire amyloid establishment isn't going to give up its dominant position easily). Also, I didn't say anything about the evidence (I don't have a "read" on the evidence, because I don't read Alz literature). My point is entirely that my priors indicate that Derek is a more reliable reader than you.

DavidSJ 3mo ago
You said the camp promoting the amyloid hypothesis has struggled greatly to come up with evidence to support its position. What did you mean by that if not a read of the quality of the evidence? Why do you continue to frame this as a choice between a single cherry-picked expert's opinion, and my own non-expert opinion? Either fairly represent the spectrum of experts' views, or decide based on the actual evidence and arguments.
- dekhn 3mo ago
  My estimate of the quality of the evidence is based on daily discussions with people who work in that field and reading summary articles in major journals. I typically don't read raw scientific articles directly- those are aimed at people in the field. Instead, my understanding comes from a synthesis of expert opinions weighted by my own priors (based on 30+ years in the field). Derek's opinion is now the prevailing one that I hear from a wide range of researchers. I've seen this happen before, btw- overturning establishment paradigms, especially ones where the underlying etiology is complex- is extremely hard and often takes decades of experimental results.
  - DavidSJ 3mo ago
    What started as an argument to ignore arguments and evidence and instead rely on authority, seems now to have morphed into an argument that we should ignore the authority of the establishment, because of your own personal assessment of the evidence (which you have not yourself read) and your own personal synthesis of conversations you've had with researchers you've personally come into contact with (despite this being apparently unrepresentative of objective measures of typical researcher opinions). Arguing from authority really only takes you so far when it ends up as an appeal to your personal experience. I'd rather you either address the arguments directly, or drop the dubious appeal to authority.
    - djdjkddkkd 3mo ago
      [dead]
    - lmeyerov 3mo ago
      I don't have a horse in this race, but for anyone who has worked in it, "science advances one funeral at a time" comes to mind here
    - novia 3mo ago
      update your priors dude
      - DavidSJ 3mo ago
        I did. I started out very skeptical, then got convinced by the quality of the evidence.
  - uxhacker 3mo ago
    Your making an argumentum ad verecundiam which even if you are right means we have to discredit it. It’s poor science to make an argument on authority, if you know the science then you should be quoting the published research and not relying on others so called expertise.
    - 3mo ago
- echelon 3mo ago
  The amyloid and tau people have had over thirty years with nothing to show for it. It's time for the inflammation / diabetes / infection / metabolic dysfunction / liver dysfunction folks to get more money to test their theories.
john_strinlai 3mo ago
>My opinion is that amyloid-as-cause moved from a majority to a minority view over the past few years, but it's not yet reflected in the literature >I don't have a "read" on the evidence, because I don't read Alz literature these two sentences seem contradictory to me. i am not sure how you would keep up on the research (to know it's moved from majority-held to minority-held view), and know that the move is not reflected in the literature, without reading the literature.
- dekhn 3mo ago
  Most scientists who are not experts in their field don't read the literature for a field directly. Instead, they synthesize their opinions about the field by consulting experts, and weighing various sorts of evidence. In my case, I work in an adjacent field and see presentations from scientists, have casual conversations with them, and read the news articles in major journals. The raw literature for alzheimer's, as well as biomed in general, is not really easily interpretable. It's rife with errors, misleading statements, and intentional obfuscation.

kurthr 3mo ago

Wow, it sure didn't take long to show a complete lack of familiarity in the field. It seems like that's going to be a real weakness with LLMs based on volumes of material that are later discovered to be semi-fraudulent and unmotivated by scientific principals. https://stanforddaily.com/2023/12/31/blockbuster-alzheimers-paper-retracted-by-former-stanford-president-after-a-decade-of-resistance/ https://stanforddaily.com/2023/12/31/blockbuster-alzheimers-...

DavidSJ 3mo ago
As noted elsewhere in this thread, which you seem not to have read, I discuss that matter in the article, which you also seem not to have read.
- deleted 3mo ago
  [deleted]
- kurthr 3mo ago
  Not only have I read it, I know people mentioned in it. There aren't very many.
  - DavidSJ 3mo ago
    You read the article in which I discuss the matter you say I was unfamiliar with?
    - thechao 3mo ago
      I'm responding to a random comment: I was in molecular biology, but >20 years ago. Your article immediately presents as someone who's acquired reading expertise in a biological/medical subfield. Second, your initial survey presents as a "brittle x": AB is the proximal cause all by itself; but, it can also be the secondary cause from many vectors. Diseases like that are (essentially) impossible to explain to the public. Also, the biological principle function is a standard trope for "good for X in the short run, bad for the person in the long run".

pcrh 3mo ago

I have direct experience of research into Alzheimer's disease, including specifically surrounding the amyloid cascade hypothesis. The strength of the amyloid hypothesis is that it is currently the only way to unify early onset AD that is caused by mutations in APP and presenilin with the pathology of both early and late set AD. The weakness is that experimental mice expressing mutated APP do not get neurodegeneration, despite showing amyloid accumulation and behavioral defects. Mice expressing mutated presenilin in contrast do get both behavioral defects and neurodegeneration, despite showing no accumulation of amyloid. "Perhaps mice are different" is the usual response/excuse. This defense is considerably weaker now, given the very modest benefits of removing amyloid from the human brain, as shown in recent clinical trials. So.... when considered rigorously, the amyloid hypothesis remains to be proven. However, it will always have its supporters until there is an alternate explation for the convergence of mutations in APP and presenilin on precisely that region of APP that generates amyloid.

DavidSJ 3mo ago
Those are amyloid-only mice. It's an amyloid+tau disease, with tau the proximate cause of neurodegeneration. Normal mice don't get tau pathology, whereas even healthy human beings do, however it stays localized until the presence of widespread amyloid pathology. Causal intervention on amyloid+tau mice is consistent with causal mediation from longitudinal human neuroimaging data: the amyloid pathology greatly accelerates tau pathology, and then this causes neurodegeneration.
- pcrh 3mo ago
  I appreciate your comment. However, a straight-forward test of the hypothesis that amyloid is the toxic (etiological) agent in AD fails when tested in mice. One may then ask, what is being remedied in the many, many, studies that claim to successfully target amyloid toxicity in mice? And is this relevant to the processes that occur in AD? Human pathology studies are limited in ability to determine causal agents because they are primarily observational, i.e. they find correlations, show that changes in certain other proteins or processes are associated, such as tau that you mention, inflammation, etc. Or as you mention, show that the pathological hallmarks of AD have a stereotypical order of appearance. However, the only human studies that can demonstrate cause in AD are genetic studies.