The mechanistic Target of Rapamycin (mTOR) signaling pathway plays a major role in key cellular processes including metabolism and differentiation; however, the role of mTOR in microglia and its importance in Alzheimer’s disease (AD) has remained largely uncharacterized. We report that selective loss of Tsc1 , a negative regulator of mTOR, in microglia in mice of both sexes, caused mTOR activation and upregulation of Trem2 with enhanced β-Amyloid clearance, reduced spine loss, and improved cognitive function in the 5XFAD AD mouse model. Combined loss of Tsc1 and Trem2 in microglia led to reduced β-Amyloid clearance and increased Aβ plaque burden revealing that Trem2 functions downstream of mTOR. Tsc1 mutant microglia showed increased phagocytosis with upregulation of CD68 and Lamp1 lysosomal proteins. In vitro studies using Tsc1 -deficient microglia revealed enhanced endocytosis of the lysosomal tracker indicator Green DND-26 suggesting increased lysosomal activity. Incubation of Tsc1 -deficient microglia ...