Abstract
Astrogliosis is increasingly recognized as a critical component of Alzheimer's disease (AD) pathology, but its precise mechanistic contribution to the interplay among amyloid-β (Aβ), tau, and neurodegeneration remains unclear. Glial fibrillary acidic protein (GFAP), a widely used biomarker of astrocytic activation, shows strong associations with both Aβ and tau pathologies; however, its causal and modulatory involvement in disease progression has yet to be fully delineated. In this study, we investigated whether plasma GFAP functions as a mediator and/or moderator of the relationships linking Aβ deposition, tau accumulation, and neurodegenerative changes in AD. Ninety-two older adults from the KBASE cohort underwent multimodal imaging including Aβ-PET, tau-PET, FDG-PET, and MRI-based hippocampal volumetry, along with blood sampling for plasma GFAP assessment. Elevated plasma GFAP levels were associated with increased Aβ and tau burden, reduced cerebral glucose metabolism, and smaller hippocampal volume, as well as poorer cognitive performance. Mediation analyses demonstrated that GFAP significantly explained the relationships between Aβ and tau, and between tau and metabolic dysfunction. Moderation analyses further revealed that GFAP strengthened the Aβ-tau association, while mitigating tau-related metabolic decline. Overall, these results support a dual role of GFAP as both a conduit and regulator of disease progression.