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<p>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.</p>

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

  • 期刊论文

  • 发表日期：

    2026年5月12日

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  • Tongyao You,
  • Yingzhe Wang,
  • Jun Xu,
  • Yanxin Zhao,
  • Sisi Peng,
  • Qi Han,
  • Xun Wang,
  • Minjie Zhang,
  • Weiwei Shen,
  • Min Guo,
  • Junjian Zhang,
  • Hailun Yu,
  • Jintai Yu,
  • Qiang Dong,
  • Mei Cui

摘要

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.