Prognostic value of plasma glial fibrillary acidic protein in cognitively unimpaired older adults: Results from the A4 study

INTRODUCTION: Plasma glial fibrillary acidic protein (GFAP), a marker of astrocytic activation, has been linked to Alzheimer's disease; however, its prognostic value in cognitively unimpaired (CU) individuals remains unclear. METHODS: We included 949 CU older adults from the A4 preclinical AD trial and its companion LEARN cohort. Baseline plasma GFAP was measured, and associations with cognitive decline (Preclinical Alzheimer's Cognitive Composite [PACC]), Clinical Dementia Rating (CDR) progression, and imaging biomarkers were assessed over 240 weeks. RESULTS: Baseline plasma GFAP was higher in females and in A4 (amyloid-positive) versus LEARN (amyloid-negative) participants. Cross-sectionally, elevated GFAP was associated with lower cognitive performance and greater amyloid burden. Longitudinally, higher GFAP predicted faster cognitive decline, increased risk of CDR progression, AD-related cortical atrophy, and amyloid conversion, with stronger effects in females. DISCUSSION: Plasma GFAP is a prognostic biomarker in CU older adults, predicting cognitive and biological changes, with stronger associations observed in females, highlighting a possible sex-specific vulnerability. HIGHLIGHTS: Elevated plasma glial fibrillary acidic protein (GFAP) predicted faster cognitive decline measured by Preclinical Alzheimer's Cognitive Composite (PACC). GFAP was associated with increased risk of progression to mild cognitive impairment. GFAP predicted conversion to amyloid positivity in amyloid-negative subjects. Higher baseline GFAP was associated with cortical atrophy in Alzheimer's disease (AD) -signature areas. Associations of GFAP with cognition and AD biomarkers were stronger in females.