Why Some People Avoid Alzheimer’s Despite Carrying a High-Risk Gene

The discovery builds on earlier research showing that some people who carry the high-risk APOE ε4 gene variant also have a rare protective mutation in FN1, which encodes the protein fibronectin. While fibronectin normally helps maintain tissue structure, excessive amounts can accumulate around blood vessels in the brain, potentially damaging the blood-brain barrier. The rare mutation appears to limit this buildup.

A new study published in Nature Aging explains how excess fibronectin may compromise this protective barrier and identifies several potential targets for future treatments.

How a Genetic Risk Factor Can Damage the Brain

The blood-brain barrier regulates the movement of substances between the bloodstream and brain tissue. It helps keep potentially harmful substances out while maintaining the conditions necessary for normal brain function. When the barrier becomes damaged or more permeable, it may contribute to inflammation and other processes associated with neurological disorders, including Alzheimer’s disease.

To investigate fibronectin’s role, the researchers analyzed human brain tissue and cerebrospinal fluid, combining genetic and epigenetic studies with single-cell sequencing and spatial imaging. They also conducted experiments using human stem-cell models, three-dimensional blood vessel cultures, zebrafish and mice.

The results pointed to a consistent pattern: the APOE ε4 variant promotes the production and accumulation of fibronectin around brain blood vessels. In mice carrying the human version of APOE ε4, researchers found nearly twice as much fibronectin in the brain as in animals carrying APOE ε3. This increase was accompanied by signs of a compromised blood-brain barrier.

Excess Fibronectin Can Disrupt the Brain’s Protective Barrier

To determine whether fibronectin directly contributes to the damage, the team increased its levels in astrocytes — specialized brain cells that help support neurons and maintain the blood-brain barrier.

The increase was sufficient to make the barrier more permeable. Conversely, reducing fibronectin improved its function. These experiments provided evidence that the protein’s excessive accumulation can actively contribute to vascular damage rather than simply appearing as a consequence of it.

The researchers also identified a molecular pathway that may explain how this happens. Excess fibronectin activates abnormal signaling through integrins, proteins that help cells respond to their surroundings, and an enzyme called focal adhesion kinase.

These signals disrupt communication involving three growth factors: VEGF, HBEGF and IGF1. Although growth factors are often associated with cellular development and repair, these molecules also help astrocytes and blood vessel cells coordinate their activities and preserve the blood-brain barrier.

When this communication breaks down, the barrier can lose its integrity, potentially making brain tissue more vulnerable to damage.

The team observed similar biological changes in human Alzheimer’s tissue and experimental models. Analyses of brain tissue and cerebrospinal fluid linked elevated fibronectin levels to inflammation in astrocytes. Genetic and gene-regulation studies also connected FN1 with blood vessel disease and changes involving VEGFA, a growth factor important for vascular health.

Together, these findings strengthen the evidence that excess fibronectin may contribute to the blood vessel damage associated with APOE ε4.

A Rare Mutation Could Point to New Treatments

The findings are significant because APOE ε4 is the strongest common genetic risk factor for Alzheimer’s disease. Approximately one in five people carries at least one copy of this variant. However, carrying APOE ε4 does not mean that a person will inevitably develop the disease.

Understanding why some carriers remain cognitively healthy could help scientists identify new ways to prevent or delay Alzheimer’s. The Columbia researchers highlight three potential therapeutic strategies:

• Preventing excessive fibronectin from accumulating around brain blood vessels.

• Blocking the abnormal cellular signals triggered by excess fibronectin.

• Restoring growth-factor signaling that helps maintain the blood-brain barrier.

Researchers are investigating these possibilities in laboratory experiments, but translating the findings into treatments will require further work.

Fibronectin performs essential functions throughout the body, including maintaining tissue structure and supporting wound healing. Any future therapy would therefore need to target its harmful accumulation or effects without interfering with these beneficial functions.

The study provides a more detailed understanding of how a major genetic risk factor may contribute to early vascular damage. It also offers potential molecular targets that could help scientists develop treatments and assess whether those treatments are protecting the brain.

Although the proposed approaches remain experimental, the findings suggest that reproducing the protection associated with the rare FN1 mutation could eventually offer a new way to defend the brain against Alzheimer’s-related damage before it becomes extensive.