We are excited to share a new preprint from the Kizil Lab titled “APOE‑ε4‑induced Fibronectin at the blood‑brain barrier is a conserved pathological mediator of disrupted astrocyte–endothelia interaction in Alzheimer’s disease.”
In this study, we uncover a previously unknown mechanism by which the APOE‑ε4 allele—one of the strongest genetic risk factors for Alzheimer’s disease—disrupts brain homeostasis. Using a combination of human postmortem tissue, zebrafish, and mouse models, the team shows that APOE‑ε4 drives excessive fibronectin accumulation at the blood–brain barrier. This fibronectin buildup compromises vascular integrity and interferes with essential communication between endothelial cells and astrocytes. Strikingly, this phenomenon is conserved across species, highlighting fibronectin as a central mediator of APOE‑ε4-induced pathology. These findings expand our understanding of how vascular dysfunction contributes to neurodegeneration and point to fibronectin as a potential therapeutic target to restore blood–brain barrier health in APOE‑ε4 carriers.
You can read the full preprint on bioRxiv here.
Our new preprint builds on our earlier Acta Neuropathologica paper that identified a rare loss-of-function variant in the FN1 gene that significantly reduces Alzheimer’s risk specifically in APOE‑ε4 homozygotes. Functional validation in models demonstrated that fibronectin loss-of-function alleviates gliovascular pathology and enhances microglial clearance—suggesting that reducing FN1 activity may mimic a protective effect against APOE‑ε4 toxicity. Our preprint now mechanistically demonstrates that the pathogenic APOE‑ε4 allele induces fibronectin accumulation around blood vessels, disrupting astrocyte–endothelial communication across species. The implication is that carriers of the protective FN1 variant are shielded from this fibronectin-driven vascular pathology. By directly connecting APOE‑ε4, fibronectin deposition, and BBB–astrocyte dysfunction, the study explains how fibronectin acts as a key mediator of ε4-associated neurovascular damage—and why loss of fibronectin function is protective. Reducing fibronectin levels appears to counteract APOE‑ε4’s vascular pathology—offering a new strategy to mimic genetic resilience and protect against Alzheimer’s in high-risk individuals.
Kizil Lab 