Single-nucleus multiomics in brains from Hispanic individuals reveal APOE-ε4 -driven disruption of focal adhesion signaling in the presence of cerebrovascular pathology

The apolipoprotein E ε4 allele ( APOE-ε4 ) is the strongest genetic risk factor for late-onset Alzheimer’s disease (AD), yet its molecular impact on cerebrovascular biology remains inconclusive, particularly in underrepresented populations with elevated vascular burden. Individuals from Hispanic ancestry experience disproportionately high rates of cerebrovascular pathology, offering a unique opportunity to investigate the mechanisms of cerebrovascular pathology in AD. Here, we performed single-nucleus RNA sequencing (snSeq) on 413,175 nuclei from 52 postmortem Hispanic brains to determine APOE-ε4 -associated cell type specific transcriptomic changes in a population with elevated cerebrovascular risk. We identified a conserved molecular signature marked by dysregulated extracellular matrix deposition and focal adhesion signaling in astrocytes. These findings were replicated in the non-Hispanic ROSMAP cohort (n = 424) snSeq. Findings were validated in isogenic human iPSC-derived astrocytes, humanized APOE targeted replacement mouse brains, and post-mortem human brains at protein and chromatin accessibility level. Our data suggest that APOE-ε4 astrocytes adopt a hyper-adhesive, mechanically rigid phenotype that may exacerbate cerebrovascular pathology.