The discovery points to a rare mutation in the FN1 gene, which produces the protein fibronectin. This mutation appears to protect blood vessels in the brain from damage associated with the Alzheimer’s risk gene APOE ε4. The findings could open a new path toward treatments designed to protect the brain’s blood-brain barrier.

The research, published in Nature Aging, builds on a study the team published two years ago. That earlier work found that some people who carry APOE ε4 also have a rare protective mutation in the FN1 gene.

Fibronectin helps support tissue structure throughout the body. However, in people with APOE ε4, excess fibronectin can accumulate around blood vessels in the brain. This buildup may weaken the blood-brain barrier, an important defense system that protects brain tissue from potentially harmful substances in the bloodstream.

The new study explains how excess fibronectin contributes to blood-brain barrier damage and identifies possible ways to interrupt the process. The findings may eventually help scientists develop treatments that recreate the protection provided by the rare FN1 mutation.

“This new study takes us from genetic clues to disease mechanisms,” says Kagan Kyzil, corresponding author of the study and professor of neuroscience in the Columbia University Vagelos College of Physicians and Surgeons’ Department of Neurology and the Taub Institute on Alzheimer’s Disease and the Aging Brain.

“We knew that changes in fibronectin could protect against Alzheimer’s disease, but we didn’t know why excess fibronectin was harmful in the first place. This study gives us the detailed mechanism, thereby giving us ideas for how to recreate the natural protection.”

How APOE ε4 may weaken the blood-brain barrier

The blood-brain barrier forms a protective boundary between the bloodstream and the brain. It is made up of tightly connected cells surrounding blood vessels in the brain. The barrier carefully controls which substances can enter brain tissue while helping maintain the conditions needed to remove potentially harmful waste products.

When the blood-brain barrier becomes damaged or overly permeable, substances that would normally be blocked can enter the brain. This disruption can contribute to inflammation and other processes associated with neurological diseases, including Alzheimer’s disease.

To investigate fibronectin’s role, the Columbia research team used several complementary approaches. Researchers performed genetic and epigenetic analyses of human brain tissue and cerebrospinal fluid, the clear fluid surrounding the brain and spinal cord.

They also used single-cell sequencing to study the activity of individual cells and spatial imaging to identify where biological changes occurred in tissues. Additional experiments involved human stem cell models, three-dimensional blood vessel cultures, zebrafish and mice.

Across the different research methods, the results pointed to the same mechanism: APOE ε4 promotes the production and accumulation of fibronectin around blood vessels in the brain.

The researchers measured nearly twice as much fibronectin in the brains of mice engineered to carry human APOE ε4 compared with mice carrying APOE ε3, another common version of the gene. The increased fibronectin accumulation was accompanied by evidence that the blood-brain barrier had become more permeable.

Scientists identify how excess fibronectin damages brain vessels

One experiment provided especially important evidence that fibronectin does not merely accumulate after blood vessels have already been damaged.

The researchers increased human fibronectin specifically in astrocytes, specialized support cells that help maintain the blood-brain barrier and support healthy brain function.

Increasing fibronectin in these cells was enough to disrupt the barrier and make it more permeable. In contrast, reducing fibronectin improved the barrier’s ability to function properly.

These findings provide experimental evidence that excess fibronectin may directly contribute to blood-brain barrier damage rather than simply appearing alongside it.

“Animal studies have allowed us to move beyond association,” says co-first author Pravesh Bhattarai, an associate research scientist in the Kizil laboratory. “Increasing astroglial fibronectin made the barrier permeable. Reducing fibronectin improved barrier function.”

The team then examined the molecular events responsible for the damage.

They found that excess fibronectin activates abnormal signals through integrins, proteins that help cells sense and respond to their surroundings. These signals also involve enzymes called focal adhesion kinases, which help regulate communication between cells.

The abnormal signaling disrupts a network of growth factors, including VEGF, HBEGF and IGF1. Although growth factors are often associated with cell development and repair, these signaling molecules also help astrocytes and vascular cells coordinate their activities and maintain a healthy blood-brain barrier.

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

“Single-cell analysis allowed us to examine this pathway in a variety of cells that maintain blood vessels in the brain,” says co-first author Elanur Yilmaz, an associate research scientist in the Kizil laboratory. “We observed the same biological patterns across experimental models and human Alzheimer’s tissue, making this mechanism particularly compelling.”

Human brain evidence strengthens the Alzheimer’s connection

The researchers also found evidence of a similar biological disruption in human samples. This suggests that the processes identified in laboratory experiments may contribute to Alzheimer’s disease in people who carry APOE ε4.

Analysis of brain tissue and cerebrospinal fluid showed that elevated fibronectin levels were associated with inflammation in astrocytes.

Gene activity and gene-regulation analyses also linked FN1 to vascular disease and to changes involving VEGFA, a growth factor that plays an important role in maintaining healthy blood vessels in the brain.

Together, these findings provide multiple lines of evidence connecting excess fibronectin with the vascular damage associated with APOE ε4.

“The convergence of these independent human data sets strengthens the case that fibronectin is part of the APOE ε4-associated vascular disease process,” says Badri Vardarajian, associate professor of neuroscience in the Department of Neurology, the Gertrude H. Sergievsky Center and the Taub Institute. Vardarajian helped discover the protective FN1 mutation.

Could a rare genetic defense lead to new Alzheimer’s treatments?

The potential significance of the discovery is substantial because APOE ε4 is the strongest common genetic risk factor for Alzheimer’s disease. About one in five people carries at least one copy of this gene variant.

However, carrying APOE ε4 does not guarantee that a person will develop Alzheimer’s disease. Studying carriers who remain cognitively healthy may reveal biological defenses that could be used for prevention and treatment.

The latest findings suggest several possible treatment strategies:

• Prevent harmful amounts of fibronectin from accumulating around blood vessels in the brain.
• Block the abnormal cell signals triggered by excess fibronectin.
• Restore growth-factor signaling so astrocytes and vascular cells can better maintain the blood-brain barrier.

Researchers are already investigating these possibilities in laboratory experiments. However, the findings are still at an experimental stage, and considerable caution will be needed before any treatment can be tested for clinical use.

Fibronectin performs important functions throughout the body, including supporting tissue structure and helping injured tissue heal. Future therapies would therefore need to target harmful fibronectin accumulation or signaling without interfering with the protein’s beneficial activities.

By identifying the molecular mechanisms involved, scientists now have a more precise framework for designing potential treatments. The findings may also help researchers determine when an intervention would be most effective and how to measure whether it is protecting the brain.

“By showing how fibronectin contributes to early vascular damage, this study provides a new therapeutic target and a potential way to measure whether treatments are working,” says Richard Mayeux, chair of the Department of Neurology and a co-investigator on the project. “Clinically, we link key genetic risk factors for Alzheimer’s disease to an earlier, potentially modifiable disease process.”

Although potential treatments based on this discovery remain experimental, the research offers a promising new direction for Alzheimer’s disease science. Instead of focusing only on damage that occurs after the disease progresses, researchers may eventually be able to recreate natural genetic defenses that protect the brain before serious damage begins.