Paired Vascular-Parenchymal Single Nuclei Sequencing Reveals Perturbed Endothelial-to-Mesenchymal Transition in Alzheimer’s Disease

The neurovascular unit (NVU) plays a crucial role in maintaining brain functions by integrating vascular cells, neurons, and glia to ensure metabolic support and blood-brain barrier integrity. While vascular dysfunction has been implicated in Alzheimer's disease (AD), the specific contributions of various vascular cell types remain understudied, partly due to challenges in isolating these cells from post-mortem tissue. In this study, we analyzed prefrontal cortex tissue from AD patients and control subjects using single-nuclei RNA sequencing to create a high-resolution atlas capturing major vascular and parenchymal cell types. Our findings reveal distinct associations between AD risk and gene expression profiles specific to pericytes, perivascular fibroblasts, and activated microglia. Functional analyses indicate that these genes converge on amyloid-related pathways, suggesting that perivascular compartments and immune modulators play significant roles in the early stages of AD pathobiology. Additionally, we identified a new endothelial-mesenchymal transition population that is diminished in AD, indicating a potential disruption in endothelial plasticity that may contribute to vascular dysfunction. Key ligand-receptor interactions between vascular and parenchymal cell types, such as ANGPT2, were found to be markedly dysregulated, highlighting potential targets that could drive NVU breakdown in AD. These findings provide a comprehensive framework for evaluating NVU cells in human disease and underscore novel links between vascular dynamics and AD pathogenesis. The study offers valuable insights into disease mechanisms and suggests new therapeutic avenues aimed at protecting and restoring the brain's neurovascular interface.