Brain endothelial cell-derived extracellular vesicles (c-BEEVs) as a promising biomarker for brain vascular pathology and cognitive decline.

Abstract

Accurate measurement of brain vascular pathology is essential for understanding its role in cognitive aging. Here we classified participants using the amyloid-tau-neurodegeneration framework in a multicenter cohort and identified cerebrospinal fluid brain endothelial-derived small extracellular vesicles (c-BEEVs) as a sensitive biomarker, which correlated with vascular risk factors and the severity of small-vessel disease. c-BEEVs showed high diagnostic performance for vascular cognitive impairment and, when combined with p-tau181, effectively distinguished vascular cognitive impairment from Alzheimer's disease. In individuals with mixed Alzheimer's disease and vascular pathology, c-BEEVs were the earliest indicators of abnormalities. It predicted cognitive decline in participants without p-tau181 pathology. To investigate the mechanistic role of c-BEEVs, we established a hypertension mouse model with elevated c-BEEVs and cognitive deficits. Brain endothelial-specific knockdown of extracellular vesicle secretion alleviated cognitive and synaptic impairment. These findings position c-BEEVs as a promising biomarker for brain vascular pathology and highlight their role in neurovascular dysfunction.