Plasma GFAP and language-network tau mediate the effect of amyloid burden on semantic fluency: A mediation analysis

Amyloid burden may relate to semantic fluency through tau and astrocytic pathways, but their contributions remain unclear.

In this cross-sectional study, we analyzed 210 Alzheimer's Disease Neuroimaging Initiative (ADNI) participants with amyloid positron emission tomography (PET), tau PET, plasma glial fibrillary acidic protein (GFAP), and animal fluency. Joint mediation models estimated indirect effects through language-network tau and GFAP, with subgroup analyses in amyloid beta (Aβ)-positive participants.

In the full sample, both tau and GFAP significantly mediated the association between amyloid burden and animal fluency, with a larger, more robust estimate for tau. Direct effects were non-significant. Among Aβ-positive participants, tau mediation remained significant, whereas GFAP mediation was attenuated. The dual-mediator model showed a significant combined indirect effect (average causal mediation effects [ACME] = -0.211). Exploratory analyses suggested possible apolipoprotein E APOE ε4 moderation of the tau-mediated pathway.

Amyloid-related semantic fluency impairment was associated with language-network tau and astrocytic reactivity, with tau the stronger mediator, supporting biomarker-defined heterogeneity in language vulnerability across the Alzheimer's continuum.