Researchers identify a natural safeguard against a key Alzheimer’s risk gene

A rare genetic protective factor may help explain why some people do not develop Alzheimer’s even when they carry a major risk gene. Researchers have now shown how a protein around the brain’s blood vessels can add to that vulnerability, and how lowering it may offer a way to help.

The Columbia University group examined fibronectin, a protein that helps maintain tissue structure. When too much of it builds up around blood vessels in the brain, it can disrupt the barrier that separates the bloodstream from brain tissue.

The study, published in Nature Aging, combined human tissue and clinical data with cell cultures, zebrafish, and mouse experiments. It points to a potential treatment route, but no therapy based on the finding has yet been shown to stop Alzheimer’s in people.

The research expands on an earlier discovery tied to APOE4, a common gene variant known to raise Alzheimer’s risk. Some people who carried the variant but remained healthy also had a rare alteration in the FN1 gene, which produces fibronectin.

That protective alteration appeared to reduce fibronectin accumulation. The new work asked why an ordinarily useful structural protein might become harmful in the brain, and whether its effects could be interrupted.

The blood-brain barrier is made of closely coordinated cells surrounding blood vessels. It regulates what can enter brain tissue, so when it is damaged, the brain may be exposed to substances and inflammatory signals that are usually kept under tighter control.

In mice carrying human APOE4, researchers found almost twice as much brain fibronectin as in mice carrying APOE3, another common variant. The higher levels were linked to signs of a leakier barrier.

When fibronectin was increased in astrocytes, the support cells that help maintain the barrier, the barrier became more permeable. Lowering fibronectin improved barrier function, providing experimental evidence that the protein plays a role in the damage.

The team traced the effect to disrupted communication between support cells and blood-vessel cells. Excess fibronectin triggered signals that interfered with the processes these cells use to keep the barrier healthy and tightly regulated.

Similar patterns were also seen in human brain tissue and in the fluid surrounding the brain and spinal cord. That strengthens the link to human disease, although observations in people cannot fully replicate the controlled conditions of laboratory models.

Future approaches could include limiting harmful fibronectin buildup or blocking the abnormal signals it sets off. Even so, fibronectin also serves important roles in normal tissue repair throughout the body, so any treatment would need to preserve those functions.

The finding offers a clearer connection between an inherited risk factor and a process in brain blood vessels that may be modifiable. Insights from people who resist the disease may help guide new protection strategies, though a successful laboratory result does not yet mean a treatment for humans.

For related reading, see articles on how a Mediterranean diet could help protect against Alzheimer’s even in people at high genetic risk, and how the MIND and Mediterranean diets are associated with fewer Alzheimer’s signs in the brain.

More background can be found in articles about the Mediterranean diet being linked to a lower dementia risk, and food, vitamins, and brain health.

Source: Columbia University Irving Medical Center.