Alzheimer’s amyloid hypothesis ‘cabal’ thwarted progress toward a cure (2019)

Re:Alzheimer’s amyloid hypothesis ‘cabal’ thwarted progress ... by throwawaymaths on Tuesday June 21, 2022 @08:26PM (#31830656)

I was lucky enough to witness the sea change in a relatively intellectually honest amyloid lab in the 2003-2009 regime. We were actively pursuing results in the amyloid hypothesis but just about every other lab meeting we were careful to mention that the hypothesis might be wrong. All of our papers say "suspected"... Around the end of that period we were getting word that the first attempt at a drug targeting amyloids was failing, and it was a common morbid joke among all of us that this was all a red herring.

~15 years ain't so bad for the skepticism to make its way out of insider speculation to relatively well accepted (drug trials take a long time).

I don't have a skin in the game with the hypothesis (I'm actually biased against it) but it is worth noting that most of the drugs tried are antibodies, which introduces the confounding factor that all antibodies elicit an inflammatory oxidative response by locally catalyzing the conversion of oxygen to ozone (oxidative inflammation is thought to also be causal to Alzheimer's), so before we completely shut the book on it we might want to control for that.

VCs are clueless, but at least they are results-driven in a relatively neutral way, though they are going to be biased toward initial selection of idiotic investments. (You pick to fund something because it's a friend of a friend, a referral, social validation, etc.)

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Re:Alzheimer’s amyloid hypothesis ‘cabal’ thwarted progress ... by ramraj07 on Tuesday June 21, 2022 @09:25PM (#31831013)

> most of the drugs tried are antibodies

But not all of them right? So what exact merit does the statement hold?

I also did my PhD in a lab that rabidly believed in a hypothesis against all emerging data (it only didn’t matter that much because it was obscure). Even when my colleagues literally disproved the hypothesis my PIs undermined it while writing the paper with globs of ambiguity (just like you mentioned) and buried the result in Figure 5 instead of Figure 1, and made him never submit it to any prominent journal. All because this result made it look like they were idiots for 20 years for blindly believing a hypothesis with zero actual data. (If interested the hypothesis being IgG gets degraded in endothelial cells and that’s where the protein that salvages them works).

I’ve had front row seats for blinded belief in what you used to believe being what drives your science and focus. I am not yet prepared to forgive any lab that actually measurably put millions at misery because of it.

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Re:Alzheimer’s amyloid hypothesis ‘cabal’ thwarted progress ... by throwawaymaths on Tuesday June 21, 2022 @11:00PM (#31831551)

I don't honestly think that anyone has been put at misery. At best we will have taken slightly longer for a cure (or maybe we'll never find one). I feel like there area few too many ethical gymnastics you have to do to blame overzealous scientists for chasing down the wrong rabbit hole. But, yes the trait in general of blinded belief (versus belief used to drive effort and focus but with self-awareness that it's just a tool) among some scientists feels uncouth. I am lucky to not have had to deal with that personally. I did see it in some neighboring labs, some of those grad students got utterly fucked and when they presented consolation thesis defenses for seven years of misery, they had the dazed look like someone who had just escaped an underground cult to see the sunlight finally.

You're right not all of them are antibodies, but the ones that aren't might not be working for "other reasons". Yes, that is a cheap way out, but I still think it's worth trying (and I don't generally believe in the amyloid hypothesis)

I'm surprised IgG isn't degraded by insulin-degrading enzyme.

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Re:Alzheimer’s amyloid hypothesis ‘cabal’ thwarted progress ... by meowface on Tuesday June 21, 2022 @08:49PM (#31830805)

These are the kinds of replies that still make HN one of the best comment sections on the internet, if looking at peaks. (The average is not great, but there's huge variance.)

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