Sex differences in astrocytic reactivity and its association with cognitive decline in cognitively unimpaired older adults

INTRODUCTION: Astrocyte reactivity may contribute to increased Alzheimers disease (AD) risk in women. Although plasma glial fibrillary acidic protein (GFAP) levels have been reported to be higher in women than in men, few studies have examined sex-specific associations 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 Alzheimers Disease Neuroimaging Initiative (ADNI) was included as a replication cohort. RESULTS: Females had higher plasma GFAP levels than males in MERI (N{equiv}584), a finding that was replicated in ADNI. In MERI, higher baseline GFAP was associated with lower A{beta}42/40 and higher p-Tau231 and NfL levels. Higher baseline GFAP was also associated with steeper longitudinal decline in global cognition and episodic memory; however, GFAP x sex x time interactions were not significant. In ADNI, higher baseline GFAP was associated with higher p-Tau217 and NfL levels and with steeper longitudinal decline in global cognition and selected executive and semantic measures, without consistent evidence of sex-specific longitudinal effects. DISCUSSION: Plasma GFAP levels were consistently higher in females across two independent cohorts. GFAP was associated with AD-related blood biomarkers and longitudinal cognitive decline, but sex did not consistently modify these associations. These findings support a role for astrocytic reactivity in early AD-related processes while underscoring the need for further replication of sex-specific effects.