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This study indicates that there's a process involving these amyloid oligomers that eventually yields cognitive impairment. But we still don't know if the amyloid oligomers directly cause the impairment or are just a byproduct or calling card. Do I have that right?

I'm trying to understand because I know amyloid beta is both uncontroversially associated with Alzheimer's and very controversial in the way it's associated - is it a direct cause or just a sideshow and massive waste of research money.

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I'm personally leaning towards the viral theory I've seen some research about. The general idea is that the brain produces these products as a defense to one of several viruses as a self defense mechanism but that those proteins may do bad things as well. Apparently population studies of people who take antiviral medications for herpes showed a significant decline in incidences of Alzheimer's. I haven't followed it closely lately so I am not sure if that is a return to baseline from an elevated risk (e.x. say that herpes increases baseline risk and treatment restores it) or if it might be generally applicable. Given that most drugs that have targeted Amyloid have failed to produce results so far, something like the Tau hypothesis or viral infection seem to me to be possibilities. Again, I haven't kept up lately so I would be happy to be "corrected" with some new things to read up on.

Yes, there's in fact good evidence that the amyloids are likely an effect rather than the cause, arising from the long history of failure of drugs aimed at the amyloids.

There is very good genetic evidence that amyloid oligomers are causative in the rarer dominantly heritable types of Alzheimer's disease.

The recent positive results of a Lecanemab phase III study, furthermore provides strong evidence that Amyloid Beta is causative in all forms of Alzheimer's disease.

https://en.wikipedia.org/wiki/Lecanemab

Biogen made the same claims about Aducanumab and there has been a lot of controversy about its' approval to say the least. Why do we believe this compound is different?

Because the results of this trial is extremely convincing. The result of the Adecanumab trials was fairly unconvincing, and it was quite possible that the positive results were due to a fluke.

The second reason is that Adecanumab did not (as far as I know) differ in approach to many other amyloid beta antibodies which have clearly failed to treat Alzheimer's in trials. Adecanumab binds to and clears amyloid beta tangles or plaques, but there is good evidence that the amyloid beta plaques are not really driving the disease.

Lecanemab is different and specifically targets a form or conformation of amyloid beta. so called protofibrils, which are more much likely to be driving the disease process.

With Lecanemab only a relatively small positive effect was able to be shown. With Aducanumab by the same companies, which works similar, even that wasn’t possible even though it’s effective against amyloid oligomers. And there are many more failed treatments targeting amyloid beta.

No matter how the causal relationships are, targeting amyloid beta for treatment does not seem to help enough for treatment.

I would be very interested how genetic evidence can rule out confounding effects.

Lecanemab had an extremely strong effect, from a statistical point of view.

The average clinical efficacy could be stronger. But Lecanemab is definitely the largest step in Alzheimer's disease research in a very long time.

Well, when you have a large number of different mutations in the amyloid beta gene, and in the genes for the machinery for cutting the precursor protein APP to amyolid beta, that all leads to early and fast progressing Alzheimer's disease, which from a pathological perspective is indistinguishable from normal Alzheimer's disease, then the evidence is quite clear.

When you then see that people who have duplicates or triplicates of the amyloid beta gene, also have a much higher risk of Alzheimer's disease and the risk increases with more duplicates, the evidence is extremely strong.

Isn’t the effect small but the significance good?

If I understood it correctly there’s no amyloid beta gene, but genes for APP an genes for proteases cutting APP. As a layman that leaves a lot of other explanations open, for instance other byproducts of the proteolysis, other breakdown mechanisms for APP, …

For use as a bio marker the question is somewhat less relevant. However the other comments answer your question well

From what I've read/seen, and take this with a grain off salt because I'm a layperson, amyloid beta is associated with things like Alzheimer's, but there are counterexamples where people have a ton of amyloid beta and no pathology, and drugs targeting it have not been very successful so far.

I think it's something that correlates with impairment, but it could be a side effect of or contribute to some other processes that are causative as opposed to being correlated with Alzheimer's/etc.

More broadly, medicine seems to strong prefer testing for specific things and linking those to pathology instead of attributing pathology to things we can't detect or don't understand, so there's been much more research trying to affect things we can measure than trying to find/figure out things we could be missing/not understand.

Does anyone know how to reconcile the amyloid-caused and not-amyloid-caused comments below?

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