A study published in Nature Aging by Columbia University researchers reports a mechanism that may explain why some APOE e4 carriers remain cognitively healthy into their 80s. The team previously found a rare protective mutation in the fibronectin (FN1) gene in some APOE e4 carriers. The new work shows how excess fibronectin damages the blood-brain barrier and points to ways to mimic that natural protection.
Using human brain tissue, cerebrospinal fluid, single-cell sequencing, spatial imaging, stem-cell models, 3D blood-vessel cultures, zebrafish, and mice, the researchers found that APOE e4 promotes fibronectin accumulation around brain blood vessels. Mice carrying human APOE e4 had nearly twice as much fibronectin in the brain as mice with APOE e3, and this was accompanied by a leakier blood-brain barrier. Increasing fibronectin specifically in astrocytes was enough to make the barrier permeable; reducing it improved barrier function.
The damage appears to occur through abnormal integrin and focal adhesion kinase signaling, which disrupts growth factors including VEGF, HBEGF, and IGF1. The authors describe the work as moving from a genetic clue to a disease mechanism and say it offers ideas for reproducing the natural protection. The source describes a single study and does not report independent replication or conflicting findings.