Associations between cerebrospinal fluid biomarkers related to endothelial dysfunction and Alzheimer’s disease
Abstract
Although associations between overt vascular injury and Alzheimer’s disease (AD) have been reported, the role of subclinical vascular injury in dementia pathogenesis remains unclear. Cerebrospinal fluid (CSF) biomarkers related to endothelial dysfunction may capture subclinical vascular impairment and provide insights into early AD pathogenesis. We examined associations of ten CSF biomarkers (PDGFRβ, Osteopontin, VCAM-1, E-selectin, MMP-2, MMP-10, MMP-3, MMP-12, MMP-9/TIMP-1 ratio and Periostin) with AD core biomarkers, brain volume, cognitive function, and risk of incident AD among 444 participants. Multivariable linear regression, linear mixed-effects models, Cox proportional hazards models, mediation analyses, and 3-year time-dependent ROC analyses were applied. All models were adjusted for demographic factors, APOE ε4 status, and vascular risk factors. Seven of ten biomarkers were significantly associated with CSF tau biomarkers, whereas two biomarkers were associated with CSF Aβ 42 . Mediation analyses suggested that CSF tau biomarkers statistically accounted for a greater proportion of the associations between MMP-10 and cognition than did Aβ 42 . Among the biomarkers examined, MMP-10 showed the most consistent associations across AD-related outcomes, including lower CSF Aβ 42 , higher CSF tau biomarkers, poorer cognitive performance, greater longitudinal brain atrophy, and increased risk of incident AD dementia. Cerebrospinal fluid biomarkers related to endothelial dysfunction and vascular injury were more consistently associated with CSF tau biomarkers than with CSF Aβ 42 in non-demented individuals. MMP-10 showed the most consistent pathological, cognitive, neuroimaging, and prognostic associations and provided incremental predictive information for incident AD dementia. These findings support further investigation of endothelial dysfunction-related and vascular remodeling pathways as potential correlates of AD progression.