Newly found genetic variant may lower risk by 71%

By Staff 8 Min Read

  • Although researchers are still unclear as to what causes Alzheimer’s disease, they do know genetics plays a role.
  • Much recent research has revolved around the study of genetic variants and their role in Alzheimer’s disease.
  • Researchers from Columbia University Vagelos College of Physicians and Surgeons in New York have identified a new genetic variant that helps defend against Alzheimer’s disease, reducing a person’s odds by up to 71%.

Researchers are still unclear as to what really causes Alzheimer’s disease, a type of dementia affecting about 32 million people globally.

However, they do know that genetics plays a role, specifically some genetic variants, which include a mutation or change in the DNA of a gene that causes it to act differently.

Searching and studying genetic variants in Alzheimer’s disease is a major area of study right now. For example, scientists have discovered that genetic variants of the APOE gene and myeloid cells 2 (TREM2) may be tied to Alzheimer’s disease.

And a study published in March 2024 identified 17 genetic variants associated with Alzheimer’s disease in five genomic regions.

Now, scientists from Columbia University Vagelos College of Physicians and Surgeons in New York have identified a previously unknown genetic variant that helps defend against Alzheimer’s disease, reducing a person’s odds of developing this condition by up to 71%.

The study was recently published in the journal Acta Neuropathologica.

For this study, researchers focused on a variant that occurs in the gene that expresses fibronectin. Fibronectin is an adhesive glycoprotein that can be found on cell surfaces and in the blood and helps with certain cell functions.

Fibronectin can also be found in the blood-brain barrier, where it helps control what moves in and out of the brain.

Previous research shows that people with Alzheimer’s disease have a higher concentration of fibronectin in their blood compared to those who do not.

The researchers believe that people who have a mutation in the fibronectin gene are protected against Alzheimer’s disease as it helps to stop the buildup of too much fibronectin in the blood-brain barrier.

“These results gave us the idea that a therapy targeting fibronectin and mimicking the protective variant could provide a strong defense against the disease in people,” study co-leader Richard Mayeux, MD, chair of neurology and the Gertrude H. Sergievsky Professor of Neurology, Psychiatry, and Epidemiology at Columbia University, noted in a press release.

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

Researchers further discovered that the protective fibronectin gene variant occurred in people who never developed symptoms of Alzheimer’s disease, although they had inherited the e4 form of the APOE gene, which previous research shows significantly increases a person’s risk of developing the disease.

Scientists analyzed the genetic data of several hundred people over the age of 70 who were also carrying the APOEe4 gene variant. Study participants were from various ethnic backgrounds and some did have Alzheimer’s disease.

After combining their study results with those from replicated studies conducted at Stanford and Washington Universities, researchers found the fibronectin gene variant lowered Alzheimer’s disease risk by 71% in people carrying the APOEe4 gene variant.

In the same press release cited above, Caghan Kizil, PhD, associate professor of neurological sciences at Columbia University Vagelos College of Physicians and Surgeons and co-leader of the study, explained:

“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. 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.”

“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 added.

“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,” he suggested.

After reviewing this study, Karen D. Sullivan, PhD, ABPP, a board-certified neuropsychologist, owner of I CARE FOR YOUR BRAIN, and Reid Healthcare Transformation Fellow at FirstHealth of the Carolinas in Pinehurst, NC, told Medical News Today she was very excited about this study and its potential.

“This research provides strong evidence that the fibronectin variant may be a novel therapeutic target in Alzheimer’s disease,” Sullivan told us.

“Even though we do have FDA-approved disease-modifying drugs for Alzheimer’s disease now with lecanemab (Leqembi), they aren’t anywhere near as powerful as we need,“ she pointed out.

“We need an agent that intervenes in the earliest stages of amyloid accumulation and I’m hopeful they are onto something with this insight. It’s exciting to think the protective effects of this gene [have] been shown to be effective in two animal models and in a population-wide human study,” Sullivant said.

“We need to study the people with the fibronectin genetic variant in more detail and understand how this genetic variant expresses itself phenotypically,” she added.

MNT also spoke with Manisha Parulekar, MD, director of the Division of Geriatrics at Hackensack University Medical Center, and co-director of the Center for Memory Loss and Brain Health and associate professor at the Hackensack Meridian School of Medicine in New Jersey, about this study.

Parulekar commented that any new discovery that may reduce the odds of developing Alzheimer’s disease is very exciting and encouraging.

“While the exact cause of Alzheimer’s disease remains unknown, several factors are believed to contribute to its development, including the accumulation of amyloid plaques and tau tangles in the brain, as well as vascular dysfunction,” she detailed.

APOE4 has been linked to increased risk of Alzheimer’s but [the] exact mechanism on why some people with this gene do not get Alzheimer’s is not known,” said Parulekar.

What we do know, she added, is “that the blood-brain barrier plays a crucial role in maintaining the health and function of the brain.”

“This study is suggesting a possible mechanism for the disruption of the blood-brain barrier, and a pathway to prevent or correct this disruption. It is exciting that we are looking at multiple pathways for the etiology of Alzheimer’s. It will be helpful to get confirmation of these findings and applications in finding potential cure or prevention of this debilitating disease,” Parulekar told us.

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