Rare Genetic Variation May Protect Against Alzheimer’s Disease
Pictured, left to right: Richard Mayeux, MD, MSc, Badri Vardarajan, PhD, MS, and Caghan Kizil, PhD, MSc.
The APOEε4 gene variant is a major genetic risk factor for developing Alzheimer's disease (AD) later in life. People with two copies of this variant are almost certain to develop the disease, yet some people with this variant do not get dementia and scientists are still figuring out why. In a recent study, a team of investigators led by Drs. Badri Vardarajan, Caghan Kizil, and Richard Mayeux analyzed the genetic data of 3,500 individuals from over 700 families of different ethnic backgrounds. Their findings, published in Acta Neuropathologica and highlighted in the CUIMC Newsroom, revealed 510 genetic variants that might protect against AD. These protective variants mainly affect the genes involved with the brain's blood barrier system. Notably, one specific variant in the fibronectin (FN1) gene stood out. Research involving over 11,000 participants from Columbia, Stanford, and Washington universities showed that this FN1 variant can reduce the risk of AD by 71% and delay its onset by about four years. It does this by reducing the buildup of certain proteins and inflammation in the brain's blood vessels. Experiments with zebrafish and human brain studies after death showed that losing FN1 function helps clear harmful amyloid proteins and improves the activity of immune cells in the brain. This groundbreaking research opens up new possibilities for treating Alzheimer's disease by targeting the brain's blood vessels.