Relationship between astrocytic reactivity and white matter integrity in the context of Alzheimer’s disease pathologies

Astrocytes exhibit reactive responses to various brain pathologies, including Alzheimer’s Disease (AD), which can have both adaptive and maladaptive effects on brain function. Here, we investigate the relationships between two protein markers of astrocytic reactivity (glial fibrillary acidic protein (GFAP) and chitinase-3-like protein 1 (YKL-40)) and white matter (WM) integrity in networks vulnerable to AD pathologies in dementia-free older adults with and without AD pathologies. We analyzed data from participants in the Alzheimer's Disease Neuroimaging Initiative (ADNI) GO/2 sample with repeated diffusion tensor imaging (DTI) sessions and baseline cerebrospinal fluid (CSF) proteomics data (n = 52 from mild cognitive impairment or healthy control). WM stability in medial temporal lobe (MTL)-involved networks was quantified using correlation coefficients of mean diffusivity between baseline and 2-year follow-up. CSF-based GFAP, YKL-40, amyloid beta 1–42 (Aβ) and phosphorylated tau at baseline were included. Episodic memory was quantified as a mean by averaging repeatedly measured composite scores. We also validated the relationships using data from local Alzheimer’s Disease Research Center (ADRC). The relationship between GFAP and WM stability was moderated by Aβ, with higher GFAP related to better stability and memory in Aβ absent group while higher GFAP related to worse ptau in Aβ present group. Higher YKL-40 levels were associated with worse WM stability regardless of Aβ levels. Additionally, our validation analysis revealed a similar moderating role of APOE4 + for the relationship between WM integrity and plasma-based GFAP. Our study contributes to understanding the intricate relationship between astrocytic reactivity, AD pathology and WM integrity. GFAP's association with WM integrity was contingent on the severity of AD pathologies (Aβ levels or APOE4 status). Conversely, YKL-40 levels suggest its detrimental role in WM integrity independent of Aβ levels given its involvement in neuroinflammatory processes.