Alzheimer’s disease (AD) is the leading cause of dementia, and while genetics is the second strongest risk factor after aging, how specific gene variants disrupt microglia, the brain’s immune cells, to drive disease progression remains poorly understood. TREM2, a master regulator of microglial function, has been studied largely through loss-of-function variants, yet we recently demonstrated that the gain-of-function mutation T96K paradoxically increases AD risk, raising critical questions related to therapies currently in clinical trials aimed at boosting TREM2. This project will use human stem cell-derived microglia and mouse models carrying distinct TREM2 mutations to map how each of them alters inflammation, cellular metabolism and aging, defining the therapeutic boundaries of TREM2 activation and revealing mutation-specific targets to guide precision medicine for AD.
