Rethinking TREM2 as a target for Alzheimer’s disease after the INVOKE-2 trial failure

When Alector announced in late 2024 that its phase 2 trial of AL002, a monoclonal antibody that targets TREM2, had failed to slow cognitive decline in Alzheimer’s disease (AD), it reignited debate over the viability of microglial targets in AD. Years of compelling genetic and preclinical research had positioned the microglial receptor TREM2 as a central player in AD pathology. Now, with the first major clinical test of a TREM2-targeting therapy falling short, the obvious question is: is TREM2 still worth pursuing?

The answer is not a simple yes or no. Instead, it depends on rethinking how this microglial receptor and its adapter, DAP12, are engaged, and recognizing that the INVOKE-2 trial may have tested the idea of TREM2 as a drug target, but not the full potential of what effective activation of TREM2 could look like in the clinic. Also, new technologies and alternative strategies suggest that the story is far from over.