We are happy to announce a new preprint from the Kizil Lab, led by first author Elanur Yilmaz, titled “Single‑nucleus multiomics in brains from Hispanic individuals reveal APOE‑ε4‑driven disruption of focal adhesion signaling in the presence of cerebrovascular pathology.”
In this study, our team analyzed 413,175 single nuclei from 52 postmortem brains with high cerebrovascular burden to uncover how APOE‑ε4 affects brain vascular biology. We found that APOE‑ε4 is associated with dysregulated extracellular matrix deposition and focal adhesion signaling specifically in astrocytes. This focal adhesion signature was not only robustly present in the Hispanic cohort but also independently replicated in the large non‑Hispanic ROSMAP cohort (n = 424), and was further validated in human iPSC-derived astrocytes, APOE-targeted mouse brains, and postmortem human tissue using protein and chromatin assays.
These results suggest that APOE‑ε4 astrocytes become hyper-adhesive and mechanically stiff, potentially exacerbating cerebrovascular dysfunction—especially critical in populations already at vascular risk. By linking APOE‑ε4 to specific astrocyte ECM and adhesion changes, this work deepens our understanding of how genetic risk translates to vascular pathology in Alzheimer’s disease. The multi-cohort, multi-platform validation underscores the robustness and generalizability of these findings.
Read the full preprint on medRxiv here.
Kizil Lab 