Researchers in Colombia have discovered a genetic mutation that reduces the chance of developing Alzheimer’s disease by up to 70%, potentially protecting thousands of people in the United States from the disease.
Discovery of protective variant may allow toxic forms of amyloid to be cleared from the brain across the blood-brain barrier, new evidence that blood vessels in the brain play a major role in Alzheimer’s disease This may support new directions in treatment. development.
“While Alzheimer’s disease may begin with amyloid deposits in the brain, disease manifestation is the result of changes that occur after the deposits appear,” said Associate Professor Kagan Kyzil, co-leader of the study that identified the variant. says the doctor. He received his PhD in Neuroscience (Neurology and Taub Institute) from Columbia University Valléros College of Physicians and Surgeons.
“Our findings suggest that some of these changes are occurring in the brain’s vasculature and could lead to the development of new types of treatments that mimic the protective effects of genes to prevent or treat disease. This suggests that it is possible.”
An attractive drug target?
The protective mutations identified in the study occur in the gene that makes fibronectin, a component of the blood-brain barrier, the lining surrounding the brain’s blood vessels that controls the movement of substances in and out of the brain.
Fibronectin is normally present in very small amounts at the blood-brain barrier, but increases in large amounts in people with Alzheimer’s disease. Variants identified in the fibronectin gene appear to protect against Alzheimer’s disease by preventing excess fibronectin from accumulating at the blood-brain barrier.
“This is a classic case of too much of a good thing,” Kizil says. “This led us to believe that excess fibronectin may be interfering with the removal of amyloid deposits from the brain.”
The researchers confirmed their hypothesis in a zebrafish model of Alzheimer’s disease and are conducting additional studies in mice. They also found that reducing fibronectin in animals increased amyloid clearance and ameliorated other damage caused by Alzheimer’s disease.
“These results give us the idea that treatments that target fibronectin and mimic protective mutants may offer strong protection against this disease in people,” said the research collaboration. said leader Richard Mayeux, MD, chair of the Department of Neurology and the Gertrude H. Sergievsky Professor. Neurology, psychiatry, and epidemiology.
Modern treatments for Alzheimer’s disease target amyloid deposits directly and are highly efficient at removing them via the immune system. However, simply removing the deposits in this way will not improve symptoms or repair other damage.
“We may need to start removing amyloid earlier, but we think it can be done through the bloodstream,” Mayu added. “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 that this protective variant is present in people who have never developed symptoms but have inherited the e4 form of the APOE gene, which significantly increases the risk of developing Alzheimer’s disease.
“These resilient people can tell us a lot about this disease and what genetic and non-genetic factors may help protect us,” said study co-leader and neuroscientist says Badri N. Vardarajan, Ph.D., assistant professor at the Gertrude H. Sergievsky Center in Neurology and the Taub Institute, who is an expert in using computational approaches to discover the gene for Alzheimer’s disease.
“We hypothesized that these resilient people may have genetic variations that protect them from APOEe4.”
To find protective mutations, researchers in Colombia sequenced the genomes of hundreds of APOEe4 carriers aged 70 and older from a variety of ethnic backgrounds, including those with and without Alzheimer’s disease. Many of the participants were northern Manhattan residents enrolled in the Washington Heights/Inwood Columbia Aging Project. This project is an ongoing study conducted by Columbia University’s Department of Neurology for more than 30 years.
The study identified variants in fibronectin, and the Columbia team published their results as a preprint for other researchers to view. Based on the Columbia University team’s observations, another group at Stanford University and the University of Washington replicated the study in an independent cohort of APOEe4 carriers, primarily of European origin.
“They found the same fibronectin variant, which confirmed our findings and gave us even more confidence in our results,” Vardarajan says.
The two groups combined data on 11,000 participants and found that this mutation reduced the odds of developing Alzheimer’s disease in APOE4 carriers by 71% and reduced the chance of developing Alzheimer’s disease by about 4% in those who eventually develop Alzheimer’s disease. It was calculated that it could be prevented for a year.
Researchers estimate that 1% to 3% of APOEe4 carriers in the United States (approximately 200,000 to 620,000 people) may carry protective fibronectin mutations.
Wide range of treatment possibilities
Fibronectin variants, although discovered in APOEe4 carriers, may protect against Alzheimer’s disease in people with other forms of APOE.
“Irrespective of APOEe4 status, there are significant differences in fibronectin levels in the blood-brain barrier between cognitively healthy people and people with Alzheimer’s disease,” says Kizil.
“Anything that reduces excess fibronectin should provide some protection, and drugs that do this could be an important step forward in the fight against this debilitating condition.”
