Stage–Specific Roles of Plasma GFAP in Linking Amyloid Cascade in Alzheimer Disease
Listed in
This article is not in any list yet, why not save it to one of your lists.Abstract
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 Aβ (Aβ42/40), Aβ 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 both cohorts, plasma GFAP mediated the association of soluble Aβ42/40 (CSF in the Knight ADRC; plasma in ADNI) with Aβ PET, as well as the association of Aβ PET with tau PET in the overall samples, which remained significant after false discovery rate (FDR) correction. Among tau-negative individuals, GFAP mediated the association between CSF Aβ42/40 and Aβ PET in Knight ADRC, but this effect did not survive FDR correction with plasma Aβ42/40 in ADNI. In Aβ-positive individuals, GFAP mediated the association between Aβ PET and tau PET burden in both cohorts, but survived correction only in ADNI. Interaction findings were partially replicated across cohorts. Exploratory plasma proteomics further revealed a GFAP-associated protein network enriched for extracellular matrix (ECM)-immune remodeling network.
DISCUSSION
These findings reveal stage-specific associations of plasma GFAP with the amyloid cascade and implicate an astrocyte-centered ECM–inflammatory axis, which may inform future diagnostic panels or targeted therapies.
Clinical trial registration
Alzheimer’s Disease Neuroimaging Initiative 3, ClinicalTrials.gov, NCT02854033 .
Article activity feed
-
Stage-Specific Roles of Plasma GFAP in Linking Amyloid Cascade in Alzheimer Disease #NeuroDegeneration 🧪🧠 https://www.medrxiv.org/content/10.64898/2026.11.03.26366374v1
-
