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

Abstract INTRODUCTION Astrocyte reactivity may contribute to the increased risk of Alzheimer’s disease (AD) in women. Plasma glial fibrillary acidic protein (GFAP), a marker of astrocytic reactivity, has been associated with AD pathology and cognitive decline. Although higher 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 comprehensive evaluation including blood biomarker sampling. RESULTS Cognitively unimpaired women exhibited higher plasma GFAP levels than men (N=548). Higher baseline GFAP was associated with worse longitudinal episodic memory performance, exclusively in women. In addition, both higher baseline GFAP and increasing GFAP levels over time were associated with lower longitudinal plasma Aβ42/40 ratio. 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. Highlights Women are at increased risk of developing Alzheimer’s disease (AD). Cognitively unimpaired women exhibited higher plasma GFAP levels than men. Higher GFAP levels were associated with longitudinal cognitive decline in women. Higher GFAP associated with greater amyloid and tau burden biomarkers in women. Increased astrocyte reactivity (GFAP) may explain increased AD risk for women. Research in Context 1) Systematic Review: Women account for approximately two-thirds of individuals with Alzheimer’s disease (AD). Longer lifespan only partially explains this higher prevalence. Astrocyte reactivity, indexed by glial fibrillary acidic protein (GFAP), has emerged as a key biological marker associated with AD risk. In preclinical and prodromal stages, higher GFAP levels are linked to cognitive decline, amyloid accumulation, tau pathology, and neurodegeneration. Few studies have investigated sex-related differences in GFAP and AD risk. 2) Interpretation: Our findings indicate that cognitively unimpaired women show higher plasma GFAP levels than men. Elevated GFAP levels in women are associated with plasma biomarkers of increased amyloid and tau burden. Higher GFAP levels are also related to longitudinal decline in global cognition and episodic memory in women. 3) Future Directions: Further studies should investigate sex-related differences in astrocyte reactivity in relation to systemic inflammation, microglial activation, brain amyloid and tau pathology, and future AD risk.