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.

The authors have declared no competing interest.

This study was supported by National Institute on Aging R01 AG067501 (Genetic Epidemiology and Multi-Omics Analyses in Familial and Sporadic Alzheimer's Disease Among Secular Caribbean Hispanics and Religious Order) (RM, BNV, CK) and National Institute on Aging RF1 AG066107 Epidemiological Integration of Genetic Variants and Metabolomics Profiles in Washington Heights Columbia Aging Project (RM, BNV, CK), Taub Institute Grants for Emerging Research (TIGER) (CK), Thompson Family Foundation Program for Accelerated Medicine Exploration in Alzheimer's Disease and Related Disorders of the Nervous System (TAME-AD) (CK), Carol and Gene Ludwig Family Foundation (CK, AJL, BNV), Toffler Scholar Program (PB), and P30 AG066462 Alzheimer's Disease Research Center (AFT). Shared Resource of the Herbert Irving Comprehensive Cancer Center (HICCC) was supported from the P30 Cancer Center Support Grant. This research was funded in part through the NIH/NCI Cancer Center Support Grant P30CA013696 and used the Genomics and High Throughput Screening Shared Resource.

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

Informed consent was obtained and all procedures were approved by the Institutional Review Board at Columbia University.

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

Yes

I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

Yes

I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.

Yes

Raw snRNA-seq and snATAC-seq data are deposited in synapse.org. Proteomics datasets are deposited in ProteomeXchange PRIDE. Accessions available upon reasonable request.