Rare FN1 mutation may limit brain-vessel damage in APOE ε4 carriers

A ScienceDaily release from Columbia University Irving Medical Center published Oct. 19 described Nature Aging research linking a rare FN1 mutation to brain-vessel resilience in APOE ε4 carriers.

Evidence grade: Early (small, animal, cell or preprint). The work matters because approximately one in five people carries at least one APOE ε4 copy, but the mechanism was tested mainly in human samples, cell systems, zebrafish and mice, not in a clinical trial.

APOE ε4 is a common gene variant associated with higher Alzheimer’s risk. Columbia researchers said some carriers also have a rare mutation in FN1, the gene for fibronectin, a structural protein that can collect around brain vessels.

“This new study takes us from a genetic clue to a disease mechanism,” Caghan Kizil, the study’s corresponding author and a professor of neurological sciences at Columbia University Vagelos College of Physicians and Surgeons, said in the release.

The proposed mechanism centers on the blood-brain barrier, the vessel lining that helps control what enters brain tissue. The release said excess fibronectin around vessels may make that barrier more permeable, a change linked to inflammation and other Alzheimer’s-related processes.

In mice engineered to carry human APOE ε4, researchers measured nearly twice as much fibronectin in the brain as in mice carrying APOE ε3, another common version of the gene. The APOE ε4 mice also showed signs of a leakier blood-brain barrier, according to the release.

The team also altered fibronectin in astrocytes, support cells that help maintain the barrier. “When we increased fibronectin in astroglia, the barrier became permeable. When we reduced fibronectin, barrier function improved,” co-first author Prabesh Bhattarai said.

Researchers used human brain material, cerebrospinal fluid, single-cell sequencing, spatial imaging, human stem-cell models, 3D vessel cultures, zebrafish and mice. The release said the same biological pattern appeared across experimental systems and human Alzheimer’s tissue.

The pathway described in the release involves abnormal signaling through integrins, proteins that help cells respond to their surroundings, and focal adhesion kinase, an enzyme involved in cell signaling. The researchers also linked the changes to growth-factor signals involving VEGF, HBEGF and IGF1.

The study cannot show that reducing fibronectin would lower Alzheimer’s risk in people, or that the rare FN1 mutation fully explains why some APOE ε4 carriers keep cognition into their 80s. The supplied release did not provide sample sizes, study duration, participant characteristics, funding details or conflict-of-interest disclosures.

The findings apply most directly to Alzheimer’s biology in people with APOE ε4 and to laboratory models of brain-vessel function. They do not support genetic testing decisions, prevention plans or treatment changes without clinical evidence.

Columbia researchers said possible future strategies include limiting harmful fibronectin buildup, blocking the abnormal signals it triggers, or restoring growth-factor communication between astrocytes and vessel cells. They also said any therapy would need to avoid disrupting fibronectin’s normal roles in tissue structure and repair.

Source: ScienceDaily article based on a Columbia University Irving Medical Center release, Oct. 19, 2026.

Atlas360 reports health research and does not provide medical advice.