This study delves into the role of astrocytes, a type of brain glial cell, in Alzheimer’s disease (AD), focusing on their involvement in clearing Amyloid beta (Aβ) and binding to tau proteins. Utilizing single-nuclei transcriptomic data from human and mouse samples, the research uncovers the diversity among astrocyte subpopulations and their transcriptomic changes in AD. A key finding is the identification of a unique astrocyte subpopulation characterized by low GFAP levels and high AQP4 and CD63 expression, which is associated with enhanced Aβ clearance and tau protein binding but is reduced in AD. This subpopulation was confirmed in both mouse models and AD patient brain samples. Additionally, the study highlights significant changes in ligand-receptor interactions between astrocytes and other cell types, indicating a complex cellular interplay in AD. This research not only advances our understanding of astrocyte heterogeneity in AD but also suggests that targeting specific astrocyte subpopulations could lead to novel therapeutic strategies for the disease.