Newly discovered genetic variant protects against Alzheimer’s disease

Columbia University researchers have discovered a genetic variant that reduces the chance of Alzheimer’s disease by up to 70 percent and may protect thousands of people in the United States from the disease.

The discovery that this protective variant appears to allow toxic forms of amyloid to leave the brain and cross the blood-brain barrier supports emerging evidence that brain blood vessels play an important role in Alzheimer’s disease and may foreshadow New directions in treatment development.

Alzheimer’s disease may begin with amyloid deposits in the brain, but the disease’s manifestations are the result of changes after the deposits appear, said study co-leader Caghan Kizil, Ph.D., associate professor of neurology. of Science from the Los Angeles College of Physicians and Surgeons (Neurology and Taub Institute).

Our results suggest that some of these changes occur in the brain’s vasculature, and we may be able to develop novel therapies that mimic the protective effects of genes to prevent or treat the disease.

Attractive drug target?

The protective variant found in the study occurs in a gene that produces fibronectin, a component of the blood-brain barrier, a lining around blood vessels in the brain that controls the movement of materials in and out of the brain.

Fibronectin is normally present in very small amounts in the blood-brain barrier, but its levels are greatly increased in Alzheimer’s patients. Variants found in the fibronectin gene appear to protect against Alzheimer’s disease by preventing the accumulation of excess fibronectin at the blood-brain barrier.

“This is a classic case of too much of a good thing,” said Kzier. “This led us to think that excess fibronectin might prevent amyloid deposits from being cleared from the brain.”

The researchers confirmed this hypothesis in a zebrafish model of Alzheimer’s disease and are conducting further studies in mice. They also found that reducing fibronectin in animals increased amyloid clearance and improved other damage caused by Alzheimer’s disease.

“These results lead us to think about the potential for… Therapies that target fibronectin and mimic protective variants could provide a powerful defense in humans.

The latest treatments for Alzheimer’s disease directly target amyloid deposits and remove them very effectively through the immune system. However, simply removing deposits in this way will not improve symptoms or repair other damage.

Mayeux added that we may need to start clearing amyloid earlier, and we think this can be done through the blood. That’s why we’re excited about the discovery of this variant in fibronectin, which could be a good target for drug development.

Protective gene discovered in people resistant to Alzheimer’s disease

Researchers found this protective variant in people who never developed symptoms but inherited the e4 form of the APOE gene, which significantly increases the risk of Alzheimer’s disease.

“These resilient people can tell us a lot about the disease,” said study co-leader Badri N. Vardarayan, Ph.D., assistant professor of neurology at the Gertrude H. Sergievsky Center. and what genetic and non-genetic factors may provide protection.

“We hypothesized that these resilient individuals might have genetic variants that protect them from APOEe4 infection.

To find protective mutations, Columbia University researchers sequenced the genomes of hundreds of APOEe4 carriers over the age of 70 from various ethnic backgrounds, including those with and without Alzheimer’s disease. Many of the participants were residents of northern Manhattan who were enrolled in the Washington Heights/Inwood Columbia Aging Project, an ongoing study conducted by Columbia University’s Department of Neurology for more than 30 years.

The study identified the fibronectin variant, and the Columbia team published their results in a preprint for other researchers to see. Building on the Columbia team’s observations, another group from Stanford University and the University of Washington repeated the study in a separate group of APOEe4 carriers, mostly from Europe.

Vardarajan said they found the same fibronectin variant, which confirmed our findings and gave us more confidence in the results.

Combining data from 11,000 participants, two groups of researchers calculated that the mutation reduced APOE4 carriers’ chances of developing Alzheimer’s disease by 71% and could delay the onset of the disease by about four years.

Researchers estimate that 1% to 3% of APOEe4 carriers, estimated to be 200,000 to 620,000 people in the United States, may also carry protective fibronectin mutations.

Broad therapeutic potential

Although the fibronectin variant was found in APOEe4 carriers, it may protect against Alzheimer’s disease in people with other forms of APOE.

Kizil said there were significant differences in fibronectin levels in the blood-brain barrier between cognitively healthy people and Alzheimer’s patients, independent of their APOEe4 status.

Any drug that reduces excess fibronectin should provide some protection, and drugs that do this could be an important step in the fight against this debilitating disease.