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Genetic Variant Reduces Alzheimer’s Risk by up to 71%

The jury may still be out about what causes Alzheimer’s, but scientists are in agreement that genetics play a part in this devastating disease. To learn more about the role of genetic variants in this progressive disease that destroys memory and impairs other important mental functions, researchers wanted to search for mutations or changes in the DNA of genes that causes them to act differently. By understanding which genetic variants increase and decrease the risk of Alzheimer’s, it is hoped that a new treatment for the disease can be developed.

The Research

A team of scientists from Columbia University Vagelos College of Physicians and Surgeons analyzed the genetic data of several hundred people over 70 who were also carrying the APOEe4 gene variant, which significantly increases one’s risk of developing Alzheimer’s. Some of the participants did have Alzheimer’s. They identified a previously unknown genetic variant that helps reduce one’s odds of developing the condition by 71%. The variant occurs in the gene that expresses fibronectin, an adhesive glycoprotein found in the blood, cell surfaces, and the blood-brain barrier. The researchers were particularly interested in the variant because previous research had shown that people with Alzheimer’s have more fibronectin in their blood. The team theorize that people with a fibronectin gene mutation are protected from the disease.

“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,” said Columbia University Neurology Chair and the Gertrude H. Sergievsky Professor of Neurology, Psychiatry, and Epidemiology Richard Mayeux, MD, who served as co-leader of the study. “We may need to star clearing amyloid much earlier and we think that can be done through the bloodstream. That’s why we are excited about the discovery of this variant in fibronectin, which may be a good target for drug development.”

Perhaps most surprising, the fact that people with the protective fibronectin gene variant never developed Alzheimer’s, even if they had inherited the e4 form of the APOE gene. Even independent of their APOEe4 status, the cognitively health participants had significantly lower concentrations of fibronectin compared to those who had developed Alzheimer’s.

“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,” explained Columbia University Vagelos College of Physicians and Surgeons Associate Professor of Neurological Sciences Caghan Kizil, PhD, co-leader of the study. “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. 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.”

Potential treatments for Alzheimer’s

Although the FDA has approved lecanemab, a disease-modifying drug for Alzheimer’s, they aren’t nearly as powerful as what’s needed to fight the disease. Alzheimer’s experts are hoping that the identification of this new genetic variant will lead to the development of an agent that intervenes at the earliest stages of amyloid accumulation.

For now, more research is needed to fully understand how the gene variant expresses itself, but the study provides some valuable insights into the direction scientists may need to go to find a cure or treatment.

“This study is suggesting a possible mechanism for the disruption of the blood-brain barrier, and a pathway to prevent or correct this disruption,” said Manisha Santosh Prurlekar, MD, who serves as the director of the Division of Geriatrics at Hackensack University Medical Center, the co-director of the Center for memory Loss and Brain Health, and associate professor at the Hackensack Meridian School of Medicine. “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.”

The study was published in the April 20, 2024, edition of the journal Acta Neuropathologica.

MBJ

Wendy Burt-Thomas writes about the brain, mental health and parenting.

Check out the original research:

https://link.springer.com/article/10.1007/s00401-024-02721-1

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