[zosima]

The genetic evidence that amyloid-beta is in some way causative of at least a subset of Alzheimer's disease is still extremely strong.

The fact that amyloid-beta binding drugs like Lecanemab and Donanemab decrease progression is also very strong evidence for the amyloid-beta hypothesis.

What seemed to be the hurdle was likely, that targeting amyloid-beta in its pathological form just wasn't easy and developers of pharmaceuticals instead focused (for unknown reasons) on the solid amyloid-beta grains in the brain.

The major reason things are moving so slowly is because of the long development times of pharmaceutical compounds. A new compound will at least have to spend 2-3 years in safety studies before being tested on its first real patient, and then for Alzheimer's, which is a slowly developing disorder, nothing short of a 2-year followup time will show efficacy unless it's truly a miracle compound.

[pcrh]

Unfortunately the evidence that targeting amyloid (e.g. Lecanemab and Donanemab) improves the symptoms of Alzheimer's disease is very weak. See the latest systematic review [0]. This does not mean however that amyloid plays no role in the disease, the treatment may simply be too late.

[0] https://www.cochrane.org/evidence/CD016297_are-medicines-ant...

[zosima]

That systematic review is unfortunately severely flawed. They pooled the old anti-amyloid antibodies (which everybody agrees are inefficacious) and were never used outside clinical trials, with the new anti-amyloid antibodies, that does show modest efficacy in reducing the speed of progression.

While these two classes of drugs target the same molecule, they are developed to target amyloid-beta in very different forms. Pooling all those drugs together, and then showing very weak effect, makes absolutely zero sense, and I hope and expect this review to be pulled soon.

[pcrh]

The point of systematic reviews is to be un-biased. So if their question is whether targeting Aβ amyloid is a valid approach they have to include the unsuccessful trails as well as those purported to be successful.

As to the trials specifically for Lecanemab and Donanemab, the benefits are not claimed to be either strong or large, even by those who support it. The current support these receive is more aligned with the concept that an improved targeting of Aβ amyloid might improve outcomes. This remains to be demonstrated.

[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.)

[rustyhancock]

Agreed, especially in some subpopulations. I think the strong case today is to research it's use in people with Dawn's syndrome (accelerated development Alzheimer's Disease due to 3 copies of the APP gene). Target it only to people with those 3 copies.

It's legimate as people with DS have a hugely increased risk of AD. Their risk increase seems likely related specifically to Amyloid. Many with DS can consent to it.

In general my completely gut feeling is that once we can target Tau we might find that targeting amyloid is needed to fully curtail progression.

[pcrh]

Agreed, using these anti-amyloid treatments at an early stage in people with a high risk of early onset Alzheimer's disease, such as those with Down's syndrome, is likely the most robust test available of the theory that Aβ amyloid is directly causative of this disease.

Trials are currently ongoing. The results should start trickling out in a few years...