Resolves to my credence in 2030.
ChatGPT summary of the debate:
"- Amyloid plaques are sticky clumps of protein that build up in the brains of people with Alzheimer's disease.
The scientific community has been divided on the role of amyloid plaques in Alzheimer's for many years.
Some researchers believe that amyloid plaques are the main cause of Alzheimer's and that removing them from the brain would cure the disease. This view is supported by studies that have shown that mice genetically engineered to produce less amyloid plaques do not develop Alzheimer's, and that drugs that reduce amyloid levels can slow down the progression of the disease in some people.
Others argue that amyloid plaques are a consequence of the disease rather than a cause, and that removing them would not cure Alzheimer's. They point to the fact that many people with high levels of amyloid plaques do not have Alzheimer's, and that some people with Alzheimer's have little or no amyloid in their brains.
There is also evidence to suggest that amyloid plaques might play a role in the spread of Alzheimer's from one brain region to another, but more research is needed to confirm this.
In recent years, the scientific community has shifted towards a more nuanced view of amyloid plaques, recognizing that they may play a role in the development and progression of Alzheimer's, but that the disease is likely caused by a complex interplay of genetic, environmental, and lifestyle factors.
More research is needed to fully understand the role of amyloid plaques in Alzheimer's and to develop effective treatments for the disease."
Feb 9, 6:15am:
Do amyloid-beta plaques cause Alzheimer's symptoms?→ Do amyloid-beta plaques cause Alzheimer's disease?Close date updated to 2030-01-01 4:59 am
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Increases in amyloid-β42 slow cognitive and clinical decline in Alzheimer’s disease trials
This is quite convincing. Turning the amyloid hypothesis on its head. If they're correct and we refocus on increasing CSF Aβ42 levels, we might reach a cure way sooner...
@adssx Higher CSF Aβ42 tends to correlate with lower Aβ in the brain on PET imaging, because it's an indication of successful clearance. A low CSF Aβ42/Aβ40 ratio has been used for years now as part of biomarker confirmation of Alzheimer's in most types of cases.
@dsj Thanks (for this and for your great article in defense of the amyloid hypothesis). Here's the author's alternative theory btw: https://academic.oup.com/brain/advance-article-abstract/doi/10.1093/brain/awaf294/8228016?redirectedFrom=fulltext&login=false (Alberto Espay is very much "anti amyloid")
Also: how does this fit into your theory? https://www.gu.se/en/news/newborns-have-elevated-levels-of-a-biomarker-for-alzheimers
@adssx Thanks for this! I spent a bunch of time studying it (and related literature). It was provocative.
I think there are a number of problems with some of the key supporting empirical claims they make, in many cases being unsupported or contradicting propositions that we have strong evidence for, most importantly their claim that autosomal-dominant Alzheimer mutations in PSEN1 mainly work via a reduction in Aβ42 production rather than an increase (or increase compared to other species). [1]
But despite that, one of their central observations is true: in both autosomal-dominant and sporadic Alzheimer's disease, Aβ42 (and its ratio to Aβ40) in CSF is eventually reduced when plaque formation occurs (even if in the autosomal-dominant case its overproduction is what led to that plaque formation in the first place [2]), and therapeutics which clear plaques also lead to CSF Aβ42 increasing, moving directionally much closer to normal levels, and cognitive benefits from such therapeutics are predicted almost as well by Aβ42 increase in CSF as by plaque reduction on PET (they say "at least" as well, but this seems wrong from their own analysis).
This is compatible with the idea that the eventual pathogenic effect of amyloid plaques (on tau pathology, etc.) is mediated by "stealing" beneficial soluble Aβ42 from CSF, rather than a more direct effect from the Aβ42 in plaque. I know of nothing to contradict this (in part because the exact mechanism of the A → T causation is still a live debate), so it seems like an interesting possibility that I will track going forward. If true, plaque clearance remains a promising therapeutic strategy, but so might be direct introduction of Aβ42 into CSF, assuming that one could somehow ensure that this new Aβ42 didn't aggregate with existing plaque (which sounds hard given that this seems to be exactly what happens in the overproduction case).
As for the ptau217 in newborns, no idea! My guess is it's an unrelated mechanism and not by itself problematic (ptau217 is an early Alzheimer biomarker in adults, but isn't inherently the same as late-stage tau pathology which includes misfolding and tangles).
[1] That contradicts what I think is fairly reliable data from other studies, including actual measurements in cerebrospinal fluid (CSF) from before plaque formation, as well as direct assessments of production rates. More importantly, it is hard to reconcile this with the known fact that adding an additional copy of APP (as in Down's syndrome) seems to produce Alzheimer pathology and eventual neurodegeneration, as does elevating amyloid production in mice, as does injecting pathological amyloid species into mice or (inadvertently) humans. Nor is there a clear explanation for why less production of the main constituent (Aβ42) of plaques should lead to an abundance of such plaques.
They support this claim of reduced production with in vitro mass spectrometry studies that they conducted, and I did not delve into the methodological weeds there (nor do I necessarily have the background to properly critique their methodology if I did), but my suspicion, based on the above, is their experimental setup is not a realistic match to the in vivo case. They also reference an exceptional PSEN2 mutation carrier with extensive plaque pathology who has so far been mostly spared from the A→T conversion (for reasons that as of yet lack clear explanation), but they incorrectly say that his CSF Aβ42 levels are high (actually, they are about where you'd expect for a mutation carrier, so he has amyloid pathology by this measure as by any other).
[2] In the Down's syndrome case they themselves explain this mechanistically: "in the APP triplication case of Down’s syndrome … overexpression leads to supersaturation, which lowers the nucleation barrier to facilitate the phase transition of soluble monomers into amyloid fibrils", a logical explanation which I think should cause them to think twice about their own theory regarding PSEN1 mutations.