The study investigates the relationship between lipid metabolism in glial cells and Alzheimer's disease (AD) pathology, focusing on the APOE4/4 genotype. Single-nucleus RNA sequencing of brain tissue from AD patients revealed a microglial state characterized by the expression of ACSL1, an enzyme associated with lipid droplet (LD) formation. ACSL1-positive microglia were most abundant in AD patients with the APOE4/4 genotype. In human induced pluripotent stem cell-derived microglia, fibrillar Aβ induced ACSL1 expression, triglyceride synthesis, and LD accumulation in an APOE-dependent manner. Conditioned media from LD-containing microglia led to Tau phosphorylation and neurotoxicity in an APOE-dependent manner. The findings suggest a link between genetic risk factors for AD, such as APOE, and microglial LD accumulation, which may contribute to neurotoxic microglia-derived factors and potentially provide therapeutic strategies for AD.The study investigates the relationship between lipid metabolism in glial cells and Alzheimer's disease (AD) pathology, focusing on the APOE4/4 genotype. Single-nucleus RNA sequencing of brain tissue from AD patients revealed a microglial state characterized by the expression of ACSL1, an enzyme associated with lipid droplet (LD) formation. ACSL1-positive microglia were most abundant in AD patients with the APOE4/4 genotype. In human induced pluripotent stem cell-derived microglia, fibrillar Aβ induced ACSL1 expression, triglyceride synthesis, and LD accumulation in an APOE-dependent manner. Conditioned media from LD-containing microglia led to Tau phosphorylation and neurotoxicity in an APOE-dependent manner. The findings suggest a link between genetic risk factors for AD, such as APOE, and microglial LD accumulation, which may contribute to neurotoxic microglia-derived factors and potentially provide therapeutic strategies for AD.