Exploring the links between amyloid, astrocytic activation, and tau biomarkers in a memory clinic cohort across the Alzheimer’s disease continuum

Neuroinflammation is increasingly recognized as a central component of Alzheimer’s disease (AD) pathophysiology. Plasma glial fibrillary acidic protein (GFAP), a marker of astrocytic activation, has emerged as a promising biomarker of AD-related pathological processes, yet its relationship with amyloid and tau biomarkers across clinically heterogeneous populations remains incompletely characterized. We investigated the associations between plasma GFAP and AD biomarkers measured in plasma and cerebrospinal fluid (CSF) in a real-world memory clinic cohort. We included 105 consecutive individuals evaluated at a tertiary memory clinic between 2023 and 2025, spanning the clinical continuum from subjective cognitive decline to dementia. Plasma GFAP, p-tau181, and p-tau217, as well as CSF Aβ42/40 ratio, p-tau181, and total tau, were quantified using fully automated immunoassays. Associations among biomarkers were assessed using Spearman correlation analyses and linear regression models. Mediation analyses were performed to explore whether plasma GFAP mediated the relationship between CSF Aβ42/40 and tau biomarkers. Sensitivity analyses adjusted for age, sex, apolipoprotein E ε4 status, and cognitive performance. Plasma GFAP concentrations were significantly elevated in amyloid-positive individuals and were inversely associated with CSF Aβ42/40 ratio. Higher plasma GFAP levels were associated with increased plasma p-tau217 and p-tau181 concentrations, and these relationships remained significant after adjustment for demographic and clinical covariates. Conversely, associations with CSF p-tau181 and total tau were attenuated or no longer significant in adjusted models. Mediation analyses demonstrated that plasma GFAP partially mediated the association between CSF Aβ42/40 and plasma p-tau biomarkers, accounting for 15–38% of the total effect. Mediation effects involving CSF tau biomarkers were weaker or not statistically significant. Plasma GFAP is closely associated with both amyloid pathology and plasma p-tau alterations across the AD clinical continuum in a real-world memory clinic population. In exploratory mediation analyses, plasma GFAP accounted for part of the association between amyloid abnormality and plasma p-tau biomarkers. These findings are consistent with the hypothesis that astrocyte-related processes may contribute to the relationship between amyloid pathology and plasma p-tau alterations, although longitudinal studies are needed to clarify the temporal and mechanistic nature of these associations.