Key points:
- Reducing fibronectin increases amyloid clearance and improves other damage caused by Alzheimer’s disease.
- Researchers identified a protective variant of the fibronectin gene that reduces the odds of developing Alzheimer’s disease.
- Based on genetic sequencing studies, the team estimates that 1% to 3% of APOE4e4 carriers in the United States may also carry the protective fibronectin mutation.
Fibronectin is a component of the blood-brain barrier that is typically present in minute amounts, but is increased in people with Alzheimer’s disease. In this study, researchers identified a variant of the fibronectin gene that reduces the odds of developing Alzheimer’s disease by preventing buildup of excess fibronectin. Their discovery, published in Acta Neuropathologica, supports emerging evidence that the blood vessels in the brain play a crucial role in Alzheimer’s disease.
Researchers utilized both a zebrafish model of Alzheimer’s disease and mouse studies to show that excess fibronectin prevents the clearance of amyloid deposits from the brain. Additionally, they found that reducing fibronectin increased amyloid clearance and improved other damage caused by Alzheimer’s disease.
Researchers then sequenced the genome of hundreds of APOEe4 carriers over the age of 70, including those with and without Alzheimer’s disease. They discovered the protective fibronectin variant in people who inherited APOEe4 —a gene form that significantly increases the risk of developing Alzheimer’s disease—but never developed symptoms.
“These resilient people can tell us a lot about the disease and what genetic and non-genetic factors might provide protection,” said study co-leader Badri Vardarajan, professor at Columbia University.
Other research groups replicated the study and combined their data with the current work. Together, they analyzed data from all 11,000 participants and calculated that the mutation reduced the odds of developing Alzheimer’s in APOE4e4 carriers by 71%. The mutation also staves off the disease by approximately four years.
The team estimates that 1% to 3% of APOE4e4 carriers in the United States—roughly 200,000 to 620,000 people—may also carry the protective fibronectin mutation. Importantly, this variant could protect against Alzheimer’s disease in people with other forms of APOE4.
“Anything that reduces excess fibronectin should provide some protection,” explained study co-leader Caghan Kizil, professor at Columbia. “A drug that does this could be a significant step forward in the fight against this debilitating condition.”