Alzheimer's disease (AD) and cerebral amyloid angiopathy (CAA) are neurodegenerative disorders characterized by the pathological deposition of amyloid-beta (A beta) in the brain. Although both conditions share common pathogenic pathways, they exhibit distinct cellular manifestations and disease progression. This study focused on the differential expression and role of astrocytic colony-stimulating factor 1 (CSF1) in these diseases. Through transcriptomic analysis of 248 brain tissue samples from the hippocampal-entorhinal system of 50 individuals, we identified a significant increase in CSF1 expression in the CA4 subfield of AD patients, contrasting with a marked decrease in CAA. Functional investigations revealed that astrocytes with elevated CSF1 levels displayed neurotoxicity associated with AD-like pathology, while reduced CSF1 expression in astrocytes was linked to vascular damage characteristic of CAA. These findings suggest that CSF1 plays divergent roles in AD and CAA, contributing to their distinct pathological profiles. Our study highlights the potential of targeting astrocytic CSF1 expression as both a differential diagnostic marker and a therapeutic approach in managing these overlapping yet distinct neurological conditions.