Alzheimer’s disease (AD) is characterized by accumulation of toxic proteins (amyloid beta and tau) in the brain. Human genetics reveals that dysfunction of microglia, the brain cells responsible for clearing debris, contributes to AD progression. Microglial activity is balanced by activating and inhibiting signals to ensure efficient debris removal while limiting collateral damage. When inhibiting signals dominate, debris removal is pathologically curtailed. We discovered a microglial inhibiting signal in human brain that is overexpressed in AD. This project uses human cells and mouse models of Alzheimer’s disease to explore ways to limit this inhibiting signal, restore microglial debris clearance and curb Alzheimer’s disease progression.