Oral rapamycin treatment in 5xFAD and hAPPNL mouse models significantly reduced amyloid-β plaque burden while improving hippocampal-dependent memory performance in Y-maze and contextual fear conditioning tests. The drug enhanced microglial lysosomal degradation and increased plaque-associated microglial density, with notably stronger effects observed in female mice compared to males. This sex-dependent response adds crucial nuance to rapamycin's therapeutic profile for neurodegenerative disease. The mechanistic insight linking mTOR inhibition to enhanced microglial clearance function represents a compelling pathway for Alzheimer's intervention, particularly given rapamycin's established safety profile from decades of clinical use in organ transplantation. However, translating these promising preclinical findings faces significant hurdles. Mouse models of amyloidosis, while valuable, don't fully recapitulate human Alzheimer's complexity, particularly the tau pathology and neuroinflammatory patterns. The sex-specific effects demand careful consideration in human trials, especially given that women comprise roughly two-thirds of Alzheimer's cases. This research reinforces growing evidence that targeting cellular clearance mechanisms rather than simply blocking amyloid production may offer more promising therapeutic avenues for this devastating disease.