• Posted April 11, 2024

Gene Discovery May Lead to Better Alzheimer's Treatments

The discovery of a gene variant that rids the brain of toxic plaques linked to Alzheimer's might lead to new treatments for the disease, researchers report.

The variant arises naturally in people who don't seem to get Alzheimer's disease despite having another gene, called APOEe4, that strongly promotes the illness.

"These resilient people can tell us a lot about the disease and what genetic and non-genetic factors might provide protection," explained study co-lead author Badri Vardarajan, an assistant professor of neurological science at Columbia University in New York City.

"We hypothesized that these resilient people may have genetic variants that protect them from APOEe4," Vardarajan added in a university news release.

The researchers believe the newly discovered gene variant may reduce the risk for Alzheimer's by more than 70% in folks lucky enough to carry it.

Breaking the blood-brain barrier

In their research, Vardarajan and colleagues conducted genomic screening on hundreds of individuals who carried the APOEe4 gene variant, which greatly raises the risk for Alzheimer's, but who had gone into old age without developing the disease.

The found a common variant shared by many of these people. It occurred in a gene charged with making fibronectin, a component used to make the "blood-brain barrier."

That's the lining that surrounds the brain and helps police which substances can get in and out.

People who develop Alzheimer's tend to produce much higher levels of fibronectin, the Columbia team noted. In contrast, folks with the newly discovered gene variant had only small amounts of fibronectin within their blood-brain barrier.

That means that certain toxins -- including amyloid plaques that are a hallmark of Alzheimer's -- can more readily escape the brain in folks who carry the newly discovered gene variant.

"Alzheimer's disease may get started with amyloid deposits in the brain, but the disease manifestations are the result of changes that happen after the deposits appear," noted study co-leader Caghan Kizil, an associate professor of neurological science at Columbia's Vagelos College of Physicians and Surgeons.

Excess fibronectin could encourage all that toxic amyloid to stay put.

"It's a classic case of too much of a good thing,"Kizil said. "It made us think that excess fibronectin could be preventing the clearance of amyloid deposits from the brain." 

People with the new gene variant may have a kind of "release valve" to let amyloid drain away in blood.

"Our findings suggest that some of these changes occur in the brain's vasculature and that we may be able to develop new types of therapies that mimic the gene's protective effect to prevent or treat the disease," said Kizil.

Earlier clearance, better treatment?

Certain newly approved drugs, such as Leqembi, create an immune system response that can help remove some amyloid from the brain. However, the effect is weak and may come too late, said study co-leader Dr. Richard Mayeux, chair of neurology at Columbia.

"We may need to start clearing amyloid much earlier and we think that can be done through the bloodstream,"Mayeux said. "That's why we are excited about the discovery of this variant in fibronectin, which may be a good target for drug development." 

The initial findings from the Columbia cohort of Alzheimer's-resistant patients have already been replicated in a group of similar patients in Europe. That study was led by researchers at Stanford and Washington universities.

"They found the same fibronectin variant, which confirmed our finding and gave us even more confidence in our result,"Vardarajan noted.  

The total number of patients studied topped 11,000, and that statistical power allowed the researchers to calculate that the gene variant cut a person's odds for Alzheimer's by 71%.

Even if Alzheimer's did develop, they estimate that the fibronectin gene variant slowed disease onset by an average of four years.

The Columbia team published its findings April 10 in the journal Acta Neuropathologica.

About 1% of all APOEe4 carriers in the United States are thought to also carry the fibronectin gene variant, the study authors noted.

"There's a significant difference in fibronectin levels in the blood-brain barrier between cognitively healthy individuals and those with Alzheimer's disease, independent of their APOEe4 status,"Kizil said. "Anything that reduces excess fibronectin should provide some protection, and a drug that does this could be a significant step forward in the fight against this debilitating condition." 

More information

Find out more about amyloid plaques and Alzheimer's disease at the Alzheimer's Association.

SOURCE: Columbia University, news release, April 10, 2024