Why some people escape Alzheimer’s despite carrying a high-risk gene
Scientists have discovered why some people with a high genetic risk of Alzheimer’s remain mentally sharp into their 80s, uncovering a rare mutation that protects the brain from harmful protein buildup. The findings reveal a potential new way to prevent early brain damage and could pave the way for treatments that mimic this natural defense.
Key points
- Columbia researchers found a rare FN1 mutation may protect APOE ε4 carriers from Alzheimer's by limiting fibronectin buildup.
- In mice with human APOE ε4, fibronectin levels were nearly twice those in mice with APOE ε3.
- Raising fibronectin in astrocytes made the blood-brain barrier leaky; lowering it improved barrier function.
Researchers at Columbia University have identified a biological mechanism that may explain why some people who carry APOE ε4, a strong genetic risk factor for Alzheimer's disease, never develop it. The findings, published in Nature Aging, center on a rare protective mutation in the fibronectin (FN1) gene.
The team found that APOE ε4 promotes the buildup of fibronectin around blood vessels in the brain, which can compromise the blood-brain barrier. The rare FN1 mutation appears to limit this accumulation and the damage it causes.
How fibronectin damages the barrier
In mice engineered to carry human APOE ε4, researchers measured nearly twice as much fibronectin in the brain as in mice carrying APOE ε3, along with signs of a leaky blood-brain barrier. Increasing fibronectin in astrocytes was enough to disrupt the barrier, while reducing it improved barrier function.
The team traced the damage to abnormal signals through integrins and focal adhesion kinase that disrupt growth factors called VEGF, HBEGF and IGF1. Analyses of human brain tissue and cerebrospinal fluid showed elevated fibronectin was associated with astrocyte inflammation.
This new study takes us from a genetic clue to a disease mechanism
— Caghan Kizil
Toward new treatments
About one in five people carries at least one copy of APOE ε4. The researchers suggest possible approaches including preventing harmful fibronectin buildup, blocking the abnormal signals it triggers, or restoring growth factor signaling.
They note that any therapy would need to avoid disrupting fibronectin's essential roles elsewhere in the body, such as supporting tissue structure and healing.
