I work in drug discovery. For the past twenty years or so, my personal analogy for this hypothesis has been a fantasy story around the days after the bombing of Dresden, when a new civilization suddenly visits Dresden and has no priors about what may have happened there. The aliens see bricks all over the place and assume that the bricks were the cause of the catastrophe. They take great efforts to pick up the bricks and save a couple of lives from the people who were covered in the ruble. The aliens build better systems to pick up bricks in the future and get ready to act next time. When a nearby city gets bombed, they quickly visit and help recover bricks saving a couple more lives. A different civilization could have instead focused on reducing the bombs or detecting and defending against the attacking airplanes.
Our immune systems are complicated, much more so than airplanes and bombs. The amyloid deposits are very likely part of an immune response, and although in principle immune responses going wild are horrible and can be fixed, it is very important to work on identifying and addressing the causal factors of this disease. There have been more therapies tested on the amyloid hypothesis that mere statistical fluctuations could explain away. I don't always agree with Derek, but I'm with him on this one. New ideas are urgently needed here, or this horrible disease will be an increasingly common end state for our aging populations.
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.
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.
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.
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.
Amyloid plaques could be part of a disease cascade. Not the root cause, in other words, but an additional downstream problem than probably still needs to be addressed.
Yes, and the fact that something like oral hygiene can influence AD would support your thesis. Often an infection in the gums/teeth can result in boils or worse in distant parts of the body. Add a dysfunctional blood brain barrier and you are screwed.
Our immune systems are complicated, much more so than airplanes and bombs. The amyloid deposits are very likely part of an immune response, and although in principle immune responses going wild are horrible and can be fixed, it is very important to work on identifying and addressing the causal factors of this disease. There have been more therapies tested on the amyloid hypothesis that mere statistical fluctuations could explain away. I don't always agree with Derek, but I'm with him on this one. New ideas are urgently needed here, or this horrible disease will be an increasingly common end state for our aging populations.