Abstract
INTRODUCTION: We investigated the effects of multiple cerebrovascular disease (CeVD) neuroimaging markers on brain functional connectivity (FC), and how such CeVD-related FC changes interact with plasma phosphorylated tau (p-tau)181 (an Alzheimer's disease [AD] marker) to influence downstream neurodegeneration and cognitive changes. METHODS: Multivariate associations among four CeVD markers and whole-brain FC in 529 participants across the dementia spectrum were examined using partial least squares correlation. Interactive effects of CeVD-related FC patterns and p-tau181 on longitudinal gray matter volume (GMV) and cognitive changes were investigated using linear mixed-effects models. RESULTS: We identified a brain FC phenotype associated with high CeVD burden across all markers. Further, expression of this general CeVD-related FC phenotype and p-tau181 contributed additively, but not synergistically, to baseline and longitudinal GMV and cognitive changes. DISCUSSION: Our findings suggest that CeVD exerts global effects on the brain connectome and highlight the additive nature of AD and CeVD on neurodegeneration and cognition. HIGHLIGHTS: Effects of multiple cerebrovascular disease (CeVD) markers on functional connectivity were studied. A global network phenotype linked to high burden across CeVD markers was identified. CeVD phenotype and plasma phosphorylated tau 181 contributed additively to downstream outcomes.