Stage-dependent associations of glial fibrillary acidic protein and chitinase-3-like protein 1 with white matter network integrity in Alzheimer's disease

Abstract

Background Astrocytes become reactive in Alzheimer's disease (AD), and fluid markers of this response, including glial fibrillary acidic protein (GFAP) and chitinase-3-like protein 1 (YKL-40), increase across the AD continuum. However, it remains unclear whether astrocytic biomarker levels relate to preserved versus disrupted white matter (WM) integrity, and whether these relationships vary by amyloid-β (Aβ) burden and apolipoprotein E ( APOE ) ε4 status. Objective To examine associations of GFAP and YKL-40 with WM integrity, AD pathology, and memory across Aβ and APOE ε4 contexts. Methods We analyzed 52 dementia-free older adults from the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort with longitudinal diffusion tensor imaging and baseline cerebrospinal fluid (CSF) biomarkers. WM integrity was assessed using network-level stability and mean diffusivity within medial temporal lobe-associated networks. Baseline CSF GFAP, YKL-40, Aβ 1−42 , phosphorylated tau (p-tau181), APOE ε4 status, and episodic memory were examined. Findings were evaluated in an independent Stanford Alzheimer's Disease Research Center sample with plasma GFAP. Results GFAP showed context-dependent associations with WM integrity and AD pathology. In Aβ-negative and APOE ε4-negative individuals, higher GFAP was associated with greater WM stability, lower mean diffusivity. In Aβ-positive and APOE ε4-positive individuals, higher GFAP was associated with higher p-tau18 rather than WM integrity. Higher YKL-40 was associated with reduced WM stability. In the validation cohort, APOE ε4 status moderated the association between plasma GFAP and WM integrity. Conclusions Astrocytic biomarkers demonstrated relationships with WM integrity and AD pathology. GFAP appeared to reflect context-dependent astrocytic responses, whereas YKL-40 was consistently associated with WM disruption.