Incorporated microglia survive for over six months, adopt ramified morphologies, express homeostatic markers, and respond dynamically to tissue injury. When engineered with synergistic APP mutations, 3BTMs recapitulate key Alzheimer’s disease hallmarks, including amyloid deposition, increased phospho-tau and neuroinflammation, with microglia shifting to disease-associated transcriptional states. Treatment with anti-amyloid immunotherapy cleared deposits and reversed disease signatures in glia. The platform provides a scalable, fully human system for studying neurodegenerative disease mechanisms and testing therapeutic interventions.