A newly discovered variant in the FN1 gene, which is responsible for making the fibronectin protein, reduces the likelihood of developing Alzheimer's by up to 70 percent. This finding could lead to more effective treatments for the disease.
Led by a team from Columbia University, researchers looked closely at a particular group of people: those with another gene variant called APOEe4 who had never developed Alzheimer's. Considering APOEe4 significantly increases the risk of getting the disease, they suspected there might be a counterbalance.
Sure enough, genome sequencing of 10,763 individuals across two groups of people, revealed the protective effects of a specific FN1 variant in people with APOEe4. The FN1 variant seems to be helping to regulate the amount of fibronectin in the brain.
"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," says neurologist Richard Mayeux from Columbia University.
Fibronectin occurs naturally in small amounts in the blood-brain barrier, a key defense for the brain and an important factor in what gets in and out of it. It's a significant area of interest for scientists studying neurodegenerative diseases like Alzheimer's.
The idea is that too much fibronectin may impair the brain's ability to wash out dangerous substances, particularly the amyloid-beta proteins that noticeably build up in the brains of people who've developed Alzheimer's.
"It's a classic case of too much of a good thing. It made us think that excess fibronectin could be preventing the clearance of amyloid deposits from the brain," says neurologist Caghan Kizil from Columbia University.
"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."
Tests using a zebrafish model of Alzheimer's backed up this hypothesis, and further tests are planned. They found that reducing fibronectin enhances amyloid clearance, suggesting a direct link to Alzheimer's pathology. Additionally, reducing fibronectin in the fish improved other Alzheimer's-related damage, such as changes to glial cells.
The researchers estimate that hundreds of thousands of people with the APOEe4 allele in the US alone have this protective FN1 variant, potentially stopping Alzheimer's from developing – though plenty more research is going to be needed to work out exactly how this gene variant is helping.
The fibronectin variant was found in people who carry APOEe4, but it may also protect people with other variants of APOE from getting Alzheimer's.
We know that people with Alzheimer's have much more fibronectin in their blood-brain barrier than people who are healthy, so it's clearly involved somehow. Once that's been established, we might be able to base treatments around it.
"We may need to start clearing amyloid much earlier and we think that can be done through the bloodstream," says Mayeux. "That's why we are excited about the discovery of this variant in fibronectin, which may be a good target for drug development."
The research has been published in Acta Neuropathologica.