Scientists have reported on the mechanism of brain protection against Alzheimer's disease

Columbia University scientists have found out how excess fibronectin protein can damage the protective barrier between blood and brain tissue in carriers of the APOE e4 variant associated with an increased risk of Alzheimer's disease. This helps explain the protective effect of a rare mutation in another gene, FN1. Why a high genetic risk does not always lead to the disease and what opportunities the discovery opens up for the development of therapy — in the material of Izvestia.

What genetic feature did the study start with?

The APOE e4 variant is one of the most significant common genetic risk factors for Alzheimer's disease. However, some of its speakers retain clarity of thought even in old age. The study of such people allows us to look for biological mechanisms that can weaken the influence of unfavorable heredity.

In 2024, researchers described a rare variant of the FN1 gene encoding fibronectin. It has been found to be associated with disease resistance in some carriers of APOE e4. In an independent analysis of 7185 people with two copies of APOE e4, one of the rare FN1 variants was associated with a 71% lower chance of Alzheimer's disease. Thus, the genetic data indicated a possible protective mechanism associated with fibronectin and brain vessels.

The next question was how exactly this protein is involved in damage to the nervous system. This is the subject of a new paper published in Nature Aging on September 11, 2026.

Why does the brain need a protective barrier

The blood-brain barrier regulates the metabolism between blood and brain tissue. Its operation depends on the coordinated interaction of vascular cells and the surrounding cells of the nervous system.

The barrier restricts the penetration of unwanted substances and helps maintain the conditions necessary for the normal functioning of the brain. If its integrity is violated, its permeability increases, which can contribute to inflammation and other pathological changes.

Fibronectin is involved in maintaining tissue structure. But its excessive accumulation around the cerebral vessels, as the study has shown, can disrupt the functioning of the protective system. The previously discovered FN1 variant is associated with the limitation of this accumulation.

Scientists have uncovered the mechanism of disruption of the membranes of neurons in the APOE4 variant

In the new work, special attention was paid to astrocytes, auxiliary cells of the nervous system that are involved in maintaining the blood-brain barrier. The researchers tested how the fibronectin they produce affects neighboring vascular cells.

What the experiments showed

The team combined several research approaches. The scientists analyzed postmortem samples of the human brain and cerebrospinal fluid, studied the genetic features and regulation of gene activity.

Separate methods allowed us to evaluate the work of different types of cells and the location of changes in tissues. In addition, models based on human stem cells, three-dimensional vascular cultures, as well as experiments on zebrafish and mice were used.

In mice with the human variant of APOE e4, the fibronectin content in the brain was almost twice as high as in animals with another common variant, APOE e3. The increase was accompanied by signs of a violation of the integrity of the blood-brain barrier.

The researchers then artificially increased the production of human fibronectin in the astrocytes of experimental models. This was enough to make the barrier more permeable. As the protein content decreased, its function improved.

These experiments have shown that excess fibronectin can directly contribute to barrier damage. The causal role of the protein was tested in experimental models; changes related to it were investigated in human samples.

How is the connection between cells disrupted?

The authors also traced the molecular chain through which fibronectin accumulation affects blood vessels. The excess protein triggers disrupted signaling through integrins— proteins that help cells perceive their surroundings—and the enzyme FAK, known as focal adhesion kinase.

Further, the work of signaling systems involving the growth factors VEGF, HB-EGF and IGF-1 is changing. These molecules help astrocytes and vascular cells coordinate their activities and maintain the integrity of the barrier.

Thus, the accumulation of fibronectin affects the interaction of several cell types. Disruption of their connection can weaken the protection of brain tissue. In experimental systems, reducing fibronectin or restoring growth factor signaling improved barrier function.

What was found in human samples

The researchers found similar changes when analyzing materials from people. Increased fibronectin content in brain and cerebrospinal fluid samples was associated with inflammatory changes in astrocytes. Genetic data and gene regulation analysis have also linked FN1 to vascular pathology and changes in VEGFA, one of the factors involved in maintaining cerebral vessels.

According to the authors, the coincidence of results from different sources reinforces the assumption of the role of fibronectin in vascular disorders associated with APOE e4. It helps to correlate the laboratory mechanism with the changes observed in Alzheimer's disease in humans.

How can the discovery be used to develop a treatment?

The researchers are considering several possible directions. One is related to the prevention of excessive accumulation of fibronectin around the cerebral vessels. The other is with blocking the disrupted cellular signals that it triggers. Another approach involves restoring the interaction of astrocytes and vascular cells through growth factor systems.

These possibilities are still being studied in the laboratory. Restoring the barrier function in an experiment does not in itself prove that a similar intervention will prevent the development of dementia or improve memory in humans.

An important task is to maintain the normal functioning of fibronectin. It is necessary for tissue structure and recovery from damage, so future therapy should selectively affect its pathological accumulation or the consequences of such accumulation.

The definition of the molecular chain gives scientists more specific guidelines: which processes to influence and which changes to evaluate the result. A promising goal is to reproduce some of the natural defenses found in carriers of a rare genetic variant.