Great article, Derek. Thanks as always. I've written about this topic a few times on my substack (for a more technical audience), but wanted to draw your attention to one post that specifically addresses GLP-1s for diseases of the brain and hits on some supplementary points to what your post holds: bigpharmasharma.com/p/0…

The biggest readout in this space is Novo's P3 Alzheimer study, which is supposed to readout some time this year. That will be a major inflection point for the future of this class. If positive, we could get an Alzheimer's label for GLP-1s within 9-12 months of that readout. Pretty monumental.

Regarding mechanism of action, my read of the literature suggests that all three of the theories you propose can co-exist, but a deeper understanding of which effects are direct or indirect (and for which molecules) is still being unveiled. For example, with the "it's a brain drug" theory, the quirk about the most popular versions of these molecules, notably tirzepitide and semaglutide, are that neither of these molecules are any good at penetrating the blood brain barrier. So if these are having central (brain) effects they are in large part operating through the gut-brain axis (is one theory).

Taking that one step further, when drug co's do design the next generation of GLP-1-based drugs that are more brain penetrant and can hit the GLP-1 receptors, which do exist even in deep brain regions where the current generation of drugs cannot penetrate, does this dial-up the brain health benefits of this class or are the indirect actions through the gut-brain axis enough? We will discover answers to this soon given the number of scientific minds, companies, and risk-on dollars flowing into this space.