We previously showed that the innate immune receptor CD33 inhibits brain amyloid beta clearance, a process that requires the ligand-binding domain. Our analysis of Alzheimer’s disease (AD) genetic datasets identified novel CD33 gene variants that are associated with AD. We generated humanized CD33 mouse models that carry either wild-type CD33 or an AD-associated mutation in the ligand-binding domain of CD33. We showed that both wild-type and mutant CD33 exhibited prominent expression in microglia that cluster around amyloid beta plaques in humanized CD33 mouse models crossed to the 5xFAD mouse model of AD. Here, we will investigate the effects of CD33 mutations in the ligand-binding domain on amyloid beta pathology, neurodegeneration and microglial cell recruitment to plaques in humanized CD33 mouse models crossed to 5xFAD mice. The proposed study will elucidate molecular mechanisms underlying microglial pathology in AD and facilitate the development of personalized treatment for AD patients carrying CD33 mutations.