In Defense Of The Amyloid Hypothesis

Many people criticize the amyloid hypothese of Alzheimer’s disease, so here’s a good article written in mostly non-technical terms that defends the hypothesis: In Defense Of The Amyloid Hypothesis

There’s a prediction market about the author’s forecast (a successful amyloid-based treatment in the next 12 years), people are rougly equally divided: Will David Schneider-Joseph's bet about Beta Amyloids and Alzheimer's end up true within 12 years? | Manifold

In the comments, someone mentioned the lithium orotate article we discussed here as well (see: Lithium Supplementation - #333 by adssx ). According to the blogpost’s author, a plausible mechanism of lithium orotate aligned with the amyloid hypothesis might be:

In the section of the paper titled Lithium and Microglial Function, they describe transcriptional changes to lithium-deficient microglia, which are immune cells that usually help clear amyloid beta from the brain - the last line of that section summarizes their findings as “Li deficiency leads to a reactive pro-inflammatory state and impaired Aβ clearance”.
So I think at least part of the causal pathway here is something like: 1) amyloid starts to build up and form plaques, which start to entangle lithium and reduce cortical lithium levels, which 2) impairs microglial function, reducing their ability to clear amyloid (and increases inflammation), leading to more plaques, and so on in a vicious feedback loop.

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I think it is a splicing disease.

The annoying truth is that there are people with a high amyloid load in their brains but no signs of dementia.
The converse is also true; there are people with dementia who, on autopsy, were found to have brains almost amyloid plaque-free.
These facts alone dictate that a simple “amyloid = dementia” hypothesis cannot be correct. It must be either discarded or modified. Introducing other factors (such as lithium) into the mix might be the right way to go.

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If amyloid deposition happens 15 years before symptom onset then you’d expect that. They die from something else (heart attack?) when still symptom free. That itself is not enough to refute the hypothesis. Also what does “no sign of dementia” mean? Were these people properly assessed by a cognitive test? Do we have their baseline level from 5 or 10y ago to know how much they should score?

This article is about Alzheimer’s disease. Not all cause dementia. As far as I know nowadays Alzheimer’s is defined by the presence of amyloid plaque so if you don’t have them on autopsy you’d be re diagnosed with another type of dementia (VaD or LBD?).

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