Targeting the protein tyrosine phosphatase PTP1B enzyme significantly enhanced microglial function, enabling these brain immune cells to more effectively clear toxic amyloid beta plaques while improving cognitive performance in Alzheimer's models. The phosphatase appears to act as a molecular brake on microglial activation, and its removal unleashed their natural cleanup capacity. This mechanism represents a departure from traditional amyloid-targeting strategies that focus on preventing plaque formation or breaking them down directly. Instead, PTP1B inhibition works by supercharging the brain's endogenous clearance machinery. The approach builds on emerging evidence that microglial dysfunction—not just amyloid accumulation—drives Alzheimer's pathology. Previous research has shown that healthy microglia can effectively manage amyloid burden, but become progressively impaired in aging and neurodegeneration. PTP1B inhibitors already exist for diabetes treatment, potentially accelerating clinical translation. However, the brain's complex inflammatory environment means enhancing microglial activity could trigger unintended consequences. The therapeutic window between beneficial clearance and harmful inflammation will require careful calibration. Success would mark a paradigm shift toward empowering rather than bypassing the brain's natural defense systems.