How some people escape alzheimer despite carrying a high risk gene

A rare genetic protection

The work builds on a discovery made by the Columbia team two years ago: some people carrying APOE ε4 also have a rare protective mutation in FN1. FN1 makes fibronectin, a protein that helps support tissue structure.

In people with APOE ε4, fibronectin can build up around brain blood vessels and may weaken the blood-brain barrier. The FN1 mutation appears to limit that accumulation and the associated damage.

Testing the barrier mechanism

The new study, published in Nature Aging, investigated how excess fibronectin affects the barrier and possible ways to interrupt the process. Researchers examined human brain tissue and cerebrospinal fluid, and used genetic and epigenetic analyses, single-cell sequencing, and spatial imaging.

The team also ran experiments using human stem-cell models, three-dimensional blood-vessel cultures, zebrafish, and mice. Across these approaches, findings indicated that APOE ε4 promotes fibronectin production and buildup around brain blood vessels.

Evidence of direct damage

Mice engineered to carry human APOE ε4 had nearly twice as much brain fibronectin as mice with APOE ε3, another common version of the gene. The greater buildup was accompanied by signs of a leaky blood-brain barrier.

Researchers increased human fibronectin in astrocytes, support cells that help maintain the barrier, and found that the barrier became more permeable. Reducing fibronectin improved its function, providing experimental evidence that excess fibronectin can contribute directly to barrier damage.

A possible treatment direction

The findings help explain how a rare genetic mutation may protect blood vessels in the brain. They also bring closer the possibility of developing a treatment that recreates the mutation’s protective effect.