Cerebrovascular Single-Nucleus RNA-Seq Reveals Heat Shock Activation and Vascular Remodeling in Alzheimer’s Disease and Primary Tauopathies

Cerebrovascular dysfunction contributes to disease progression in Alzheimer’s disease (AD) and primary tauopathies, yet molecular alterations within vascular cell populations remain poorly understood. We performed single-nucleus RNA sequencing of postmortem human inferior temporal gyrus to characterize transcriptomic changes across cerebrovascular cell types in AD and primary tauopathies, including corticobasal degeneration, Pick’s disease, and progressive supranuclear palsy. Differential expression analyses revealed predominantly disease-specific transcriptional programs across vascular cell populations. However, genes involved in the heat-shock response were consistently upregulated across all diseases, suggesting a conserved cerebrovascular stress response during neurodegeneration. We also report extensive cerebrovascular remodeling taking place in AD compared with primary tauopathies and identified a dysregulation of genes within AD genome-wide association study (GWAS) loci in cerebrovascular-associated cells. Transcriptomic findings were validated using tissue clearing, light-sheet microscopy, and immunofluorescence quantification of vascular markers. We highlight shared and disease-specific vascular mechanisms in neurodegeneration with potential for newly redefined targeted therapies.