Atypical astrocytes (AtAs) are a distinct subset of non-reactive astrocytes in the brain characterized by dramatically diminished expression of excitatory amino acid transporters (GLAST, GLT1) and other astrocytic proteins. Our ongoing research on the development and progression of AtAs in naïve wild type (WT) mice has shown significant regional and age effects. We have also shown that brain tissue from confirmed Alzheimer’s Disease (AD) patients, as well as healthy controls, have areas of presumptive AtAs. This study aims to further explore the role of AtAs in AD pathology utilizing the APPNL-G-F mouse model of AD. Quantification in APPNL-G-F mice shows AtAs in the hippocampus by 2 months of age, a significantly earlier time point compared to the hippocampus of WT mice, where AtAs do not develop until after 4 months of age. Analysis of mice older than 1 year also shows increased hippocampal AtA presence in APPNL-G-F compared to WT. Key astrocytic proteins decreased in AtAs have been linked to AD, such as Aquaporin-4, a water channel that aids in clearing excess Aβ peptides from the brain and has been shown to mislocalize in human and mouse models of AD. Ongoing work examines changes of Aquaporin-4 in the normal astrocytes and AtAs to determine if it may play a role in astrocytic dysfunction. Loss of GLAST and GLT1 occurs in human AD, but any association with AtAs is unknown. This work sheds light on the intricate interplay between AtAs, normal aging and AD-related pathologies, including astrogliosis and Aβ-plaque formation.