Can we catch the second loach employing BACE1 inhibition, even as the first one might be escaping?

[...]phase III clinical trials of several BACE1 inhibitors were discontinued due to a lack of significant improvement or even worse outcomes in memory scores and non-negligible adverse effects 4. The possibilities are that: (i) the amyloid hypothesis, which has been considered highly plausible for ˜20 years, is wrong, and that Aβ formation is not the cause of dementia in AD, but is instead just a marker; (ii) the intervention is too late to prevent AD progression and earlier inhibition of BACE1 might thus be effective; (iii) the off-target effects of BACE1 inhibitors mask the benefits; and (iv) Aβ42 has an important physiological function(s), and reducing its activity too strongly might be harmful 5. Interestingly, neuronal BACE1 knock-in in mice reportedly resulted in the induction of both weight loss and diabetes 6. [...]the effects of BACE1 inhibitors on weight loss might be augmented were this molecule to be inhibited only outside the brain.