[pfisherman]

I don’t quite follow the reasoning behind this being “unbiased”. Studies must be designed to answer specific research question. What is the question being asked by the study in question. If the question being asked is whether AB the right target (in humans), then it would need to consider other forms of human evidence, such as genetic evidence, alongside alternative explanations of failure — bad molecule, wrong isoform, bad cohort selection, etc.

[pcrh]

The question asked in the Cochrane review linked to above is whether there is evidence that current treatments targeting amyloid provide relief. Their conclusion is that the effect is too small to be considered beneficial. Especially when considering the undoubted side-effects, which include edema and micro-bleeding in the brain.

It doesn't ask whether amyloid is causative of the disease.

[zosima]

I wonder. Because if that was the question, why would they include anti-amyloid treatments that were never approved and are not part of any current treatment regimen and dilute the real effect of the approved antibodies? (Not that the approved antibodies are a silver bullet, but clearly they have some positive effect.)

[pcrh]

The Cochrane review did not ask the question of whether Lecanemab (for example) worked, it asked the more general question of whether targeting amyloid worked. If targeting amyloid, generally, worked you might expect all approaches to targeting amyloid to show some efficacy. So they included all those for which clinical trials had been conducted. Obviously some treatments didn't pass the threshold required and so were not subsequently approved. If you only included successful trials you would bias the outcome.

It's possible, of course, that some methods of targeting amyloid might work where others failed. But even those that claim success (Donanemab and Lecanemab) have a very modest benefit.

[zosima]

Yes, the new anti-amyloids are not a revolutionary therapy. But they do have a small but definite effect on disease-progression. (something which in a highly noisy indication like Alzheimer's may actually mean a lot more to the patients than it seems by looking at the data. E.g. donepezil and memantine have very modest effects too, but patients and caregivers are still surprisingly positive about them).

And since these were developed using different methods and epitopes, it does not make sense to pool them together when doing a comparison. It's obvious that if you combine modestly beneficial compounds and compounds with zero beneficial effect then the mean effect will be worse than the modestly beneficial compounds.

And when you do so just because they were aimed at the same molecular target, not even considering if anyone claims that the old, unapproved antibody-therapies, with no positive studies to support them, have any effect, what you are doing is somewhere between extreme ignorance and deception.

[pcrh]

All the trials included in the Cochrane review demonstrated removal of Aβ amyloid from the brain. Side effects were relatively modest, except for edema and micro-bleeds. So they are all legitimate tests of the hypothesis that removing Aβ amyloid would be beneficial.

[pfisherman]

No you would not expect all efforts to target AB to work. You can have the right target and the wrong molecule. Look at GLP1s as an example. Multiple pharma companies tried GLP1 receptor agonists for more than a decade and it was not until recently that Novo and Lilly got them to work.

[pcrh]

The first GLP-1 receptor agonist to enter clinical trials was exenatide by Amylin Pharmaceuticals. It worked from the get go.

[zosima]

But has only weak/moderate effect on weight loss compared to semaglutide, tirzepatide and retatrutide.

Alzheimer is a lot more difficult to measure than weight and amyloid-beta in the brain obviously significantly harder to target than the GLP-1 receptor in the body.

Also, a review pooling together all GLP-1's (including those that failed in development) and concluding that they as a class have only moderate or weak effect on weight loss, would obviously be badly misleading.