Stage‑Specific Roles of Plasma GFAP in Linking Amyloid Cascade in Alzheimer Disease

INTRODUCTION: Astrocytic reactivity, measured by plasma glial fibrillary acidic protein (GFAP), is robustly elevated across the Alzheimer disease (AD) continuum, yet its relationship with the amyloid cascade remains poorly understood. METHODS: We integrated plasma GFAP with multimodal AD biomarkers, including cerebrospinal fluid (CSF) or plasma amyloid-beta (Abeta42/40), amyloid and tau positron emission tomography (PET), structural MRI, and clinical severity, across a discovery cohort (Knight Alzheimer Disease Research Center, n=278) and an independent replication cohort (Alzheimer's Disease Neuroimaging Initiative, n=236). RESULTS: In the overall samples of both cohorts, plasma GFAP statistically mediated the associations between soluble Abeta42/40 and amyloid PET and between amyloid PET and tau PET; both remained significant after false discovery rate (FDR) correction. In tau-negative individuals, the indirect association between soluble Abeta42/40 and amyloid PET remained significant after correction only in Knight ADRC. In amyloid-positive individuals, the indirect association between amyloid PET and tau PET remained significant after correction only in ADNI. Interaction findings were not consistently replicated across cohorts, either before or after correction. Plasma proteomics identified a GFAP-associated protein network enriched for extracellular matrix and immune-related pathways. DISCUSSION: These findings support associations of plasma GFAP with amyloid and tau biomarkers within A/T-defined groups and identify GFAP-associated extracellular matrix and inflammatory protein signatures that warrant further investigation.