[DavidSJ]

The hypothesis that amyloid is simply a downstream effect, not a cause, is of course worth considering, and where my mind was at when I first approached the literature skeptically. The widespread presence of amyloid-beta plaques in Alzheimer's disease has been known since 1906, but the field didn't adopt the amyloid hypothesis for decades precisely because of this possibility. But then in the early 1990's, strong genetic causal evidence emerged, which is why the amyloid hypothesis emerged at that time. Other important causal evidence has emerged since, especially that tau pathology (the proximate cause of neurodegeneration) is causally downstream of amyloid pathology, which we know from many lines of evidence now. (See the article for a lot more detail on all this, if you are curious.)

As for the possibility that the successes of amyloid therapies might be explicable by chance, this is highly implausible. Only three (aducanumab, lecanemab, and donanemab) of a dozen or more amyloid therapies successfully cleared plaque, and it is precisely those three that achieved a slowdown of cognitive decline in phase 3 trials (with aducanumab succeeding in only one of its two, but with the others succeeding in their only phase 3), several of which with p-values below 0.001. This is not p-hacking or reporting bias.

[pama]

Regarding lack of p-hacking. The placebo arm of blinded trials breaks when your brain can detect a medication. The effect is tiny in these studies; approval was rushed to give hope to patients. The drug was discontinued later.

[DavidSJ]

The drug was discontinued later.

You're thinking of aducanumab. Lecanemab and donanemab have been in widespread use for several years now, and open-label extensions vs. external controls showing increasing benefits over longer treatment durations.

[stinkbeetle]

Would you expect progression to cease if not reverse if the cause was cleared?

[DavidSJ]

Not reverse; the neurons have died.

Cease, yes, if the cause is removed early enough. But if you intervene too late (once symptoms are detectable), then the downstream tau pathology, which is what directly kills neurons, likely spreads on its own via a prion-like mechanism.

So far, no clinical trial has completed prior to clinical onset for an antibody which actually removes plaque. This is probably the main reason only 30% slowdown has been achieved so far. The donanemab prevention trial is due to complete next year. That will be an important one to watch.