Sex-specific associations between astrocytic reactivity and cognitive decline in unimpaired elderly

INTRODUCTION: Astrocyte reactivity may contribute to increased Alzheimer's disease (AD) risk in women. Although higher plasma glial fibrillary acidic protein (GFAP) levels have been reported in women, few studies have investigated sex-specific relationships with other plasma AD biomarkers and cognition. METHODS: Participants were enrolled in the Memory Education and Research Initiative, a longitudinal community-based cohort, and underwent evaluation including blood biomarker sampling. The Alzheimer's Disease Neuroimaging Initiative (ADNI) was included as a replication cohort. RESULTS: Unimpaired women exhibited higher plasma GFAP levels than men (N=584). Higher baseline GFAP was associated with worse longitudinal episodic memory, exclusively in women. In addition, both higher baseline and increasing GFAP levels over time were associated with lower longitudinal plasma Aβ42/40 ratio. The key results were replicated in the ADNI cohort. DISCUSSION: These findings suggest that astrocytic reactivity is more pronounced in women and may contribute to sex-specific vulnerability to AD-related pathology and cognitive decline.