Linking trajectories of cerebrovascular remodeling and dysfunction to cross-species brain vessel transcriptome in Alzheimer’s disease

Growing evidence implicates dysfunctional brain vasculature occurring early in Alzheimer’s disease (AD) progression. Few studies have attempted to bridge transcriptomic signatures with early neuroimaging observations of vascular abnormalities. We leveraged longitudinal in vivo imaging of the cerebrovascular tree in APP/PS1 mice to identify when vascular abnormalities emerge, followed by bulk RNA-seq of isolated brain vessels at this time point. At 9–11 months of age, AD mice exhibited microvascular remodeling and dysfunction, including increased tortuosity, decreased capillary blood flow and reduced vascular density. Enriched gene pathways highlighted increased neuroinflammation, dysfunctional angiogenesis, and deficits in actin-mediated muscle contractility. Mapping transcriptional changes to a mouse vascular atlas implicated endothelial cells and microglia in impaired angiogenesis, while mural cells showed actin-filament and ion channel deficits. Mapping to a human vascular atlas identified translational targets to alleviate actin-mediated contractility deficits. Our integrated framework advances cerebrovascular biomarker understanding and informs early-stage AD therapeutic targets.