Shared and disease-specific human brain vascular signatures in Alzheimer's disease, frontotemporal dementia, and Huntington's disease

Abstract

The blood-brain barrier (BBB) plays a central role in brain function and is increasingly implicated in neurodegenerative disease. Major neurodegenerative disorders, including Alzheimers disease (AD), frontotemporal dementia (FTD), and Huntingtons disease (HD), share overlapping pathological features. Yet, the extent to which these diseases converge or diverge at the level of BBB-associated cell types remains poorly understood. Here, we performed a comparative analysis of vessel-enriched human brain transcriptomic datasets across AD, FTD, and HD to define shared and disease-specific neurovascular alterations. We identify a partially conserved transcriptional signature of vascular dysfunction across all three diseases, alongside disease-specific changes in endothelial, pericyte, and perivascular cell populations. Endothelial remodeling was most prominent in capillary and venous segments, highlighting segment-specific vulnerability along the arteriovenous axis. Notably, we identified two molecularly distinct human pericyte subtypes across all three datasets and found a consistent reduction in the matrix-type pericytes (M-peri) fraction, suggesting a selective decline. Cell-cell communication analysis further revealed reorganized endothelial-pericyte signaling networks, with prominent alterations in extracellular matrix-associated pathways, including LAMININ, COLLAGEN, FN1, and NCAM, together with changes in contact-dependent and vascular signaling pathways such as NOTCH and VEGF. Together, our findings define shared and disease-specific neurovascular mechanisms across major neurodegenerative disorders and highlight BBB-associated pathways as central features of neurodegeneration, providing a framework for future diagnostic and therapeutic strategies.