[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.

[pcrh]

If you grouped all GLP-1 agonists that had entered clinical trials, they would be shown as successful [0]. No GLP-1 receptor agonist has failed to reduce appetite in clinical trials, but some were better than others.

The point about the anti-amyloid trials is that they all succeeded in removing amyloid. But they did not improve cognition, and only some resulted in a slightly slower rate of decline in cognition (people still declined).

[0] https://pubmed.ncbi.nlm.nih.gov/39841962/

>Forty-seven RCTs were included, with a combined cohort of 23,244 patients. GLP-1 RAs demonstrated a mean weight reduction of -4.57 kg (95% CI -5.35 to -3.78), mean BMI reduction of -2.07 kg/m2 (95% CI -2.53 to -1.62), and mean waist circumference reduction of -4.55 cm (95% CI -5.72 to -3.38) compared with placebo.

[zosima]

This is ridiculous.

Your meta review has like 80%-90% of the studies on semaglutide and liraglutide. When finding random effect per drug, they even say this:

> Hence, the drugs eligible for meta-regression were semaglutide (subcutaneous injection, once weekly) and liraglutide (subcutaneous injection, once daily), which both showed a dose-dependent treatment effect in terms of weight and BMI.

And the class-effect is much more modest than semaglutide by itself would have shown, exactly as I said. What is the point?

[pcrh]

Both meta-analyses above cover all eligible clinical trials for the respective strategies, targeting the GLP-1 receptor, or targeting amyloid.

For the GLP-1 strategy, Table 1 in the above paper shows that all drugs were clearly effective. Some were better than others.

For the amyloid strategy, only some of the drugs were effective, and that efficacy was very weak, even when all the drugs removed amyloid. This brings into question the hypothesis that removing amyloid would alleviate AD, i.e. the slender benefits of Lecanemab might not be caused by amyloid removal. The same cannot be said for the GLP-1 receptor agonists.