Plasma glial fibrillary acidic protein as a mediator of amyloid‐associated cognitive decline over 4‐year follow‐up in pre‐dementia stages

Abstract INTRODUCTION The mechanism linking amyloid beta (Aβ) pathology to cognitive decline in pre‐dementia stages remains unclear. METHODS We performed mediation analysis in 223 non‐demented adults (4‐year follow‐up) to assess plasma glial fibrillary acidic protein (GFAP), phosphorylated tau (p‐tau)181, p‐tau217, and peripheral inflammatory ratios as mediators of Aβ (18F‐florbetapir positron emission tomography)‐related cognitive decline and hippocampal atrophy. RESULTS Plasma GFAP significantly mediated Aβ‐related multi‐domain cognitive decline (accounting for 17.70% to 23.77% of the total effect) and hippocampal atrophy (specifically in the subgroup aged ≤ 70 years). Although both p‐tau181 and p‐tau217 were correlated with cognitive decline, they did not function as significant mediators of Aβ’s effects. Peripheral inflammatory ratios demonstrated no significant association with Alzheimer's disease (AD) progression. DISCUSSION Plasma GFAP is a key mediator and promising early biomarker for pre‐dementia AD.