Astrocyte–vascular interplay in Alzheimer's disease pathology: Novel insights into stage‐specific biomarkers and therapeutic targets

INTRODUCTION: We examined how neurovascular and astrocytic response alter cognition in Alzheimer's disease (AD). METHODS: Cognitive scores, biomarkers of AD and astrocytic activation, vascular factors, and brain structure data from 693 Alzheimer's Disease Neuroimaging Initiative (ADNI) participants were analyzed using analysis of covariance (ANCOVA), multiple linear and cox regression, mediation and mixed models. RESULTS: Cerebrospinal fluid (CSF) vascular endothelial growth factor (VEGF)-C levels varied significantly across cognitive stages (normal cognition [CN], mild cognitive impairment [MCI], and AD). Vascular factors showed stage-specific patterns with amyloid beta (Aβ) and tau pathology. Higher CSF VEGF-C and angiotensin-converting enzyme (ACE) correlated with better cognition and milder brain atrophy. CSF ACE was also associated with slower decline and lower AD risk. The effect of Aβ pathology on cognition was mitigated by CSF VEGF-C, whereas tau pathology and neurodegeneration were mitigated by CSF ACE. Independently, these CSF factors mediated the association between CSF glial fibrillary acidic protein (GFAP) and cognition. Astrocytic biomarkers mediated AD pathology-vascular links. DISCUSSION: Dynamic astrocyte-vascular interplay in AD pathology could influence cognition, considered as a potential therapeutic target.