The researchers have discovered a genetic variant that reduces the odds of developing Alzheimer’s disease by up to 70% and may be protecting thousands of people in the United States from the disease. 

The discovery of the protective variant, which appears to allow toxic forms of amyloid out of the brain and through the blood-brain barrier, supports emerging evidence that the brain’s blood vessels play a large role in Alzheimer's disease and could herald a new direction in therapeutic development. 

“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,” says  a co-leader of the study that identified the variant.
  
“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.” 

The protective variant identified by the study occurs in a gene that makes fibronectin, a component of the blood-brain barrier, a lining surrounding the brain’s blood vessels that controls the movement of substances in and out of the brain. 

Fibronectin is usually present in the blood-brain barrier in very minute amounts, but it is increased in large amounts in people with Alzheimer’s disease. The variant identified in the fibronectin gene seems to protect against Alzheimer’s disease by preventing the buildup of excess fibronectin at the blood-brain barrier. 

"It’s a classic case of too much of a good thing,” the author says. “It made us think that excess fibronectin could be preventing the clearance of amyloid deposits from the brain.” 

The researchers confirmed that hypothesis in a zebrafish model of Alzheimer’s disease and have additional studies in mice underway. They also found that reducing fibronectin in the animals increased amyloid clearance and improved other damage caused by Alzheimer’s 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,” says the study co-leader. 

The newest treatments for Alzheimer’s disease target the amyloid deposits directly and are very efficient at removing the deposits via the immune system. However, simply removing the deposits this way doesn’t improve symptoms or repair other damage.  

“We may need to start clearing amyloid much earlier and we think that can be done through the bloodstream,” the author adds. “That's why we are excited about the discovery of this variant in fibronectin, which may be a good target for drug development.” 

The researchers discovered the protective variant in people who never developed symptoms but who had 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 the disease and what genetic and non-genetic factors might provide protection,” says another study co-leader. 
 
"We hypothesized that these resilient people may have genetic variants that protect them from APOEe4.” 

To find protective mutations, the researchers sequenced the genomes of several hundred APOEe4 carriers over age 70 of various ethnic backgrounds, including those with and without Alzheimer's disease.

The study identified the fibronectin variant, and the team publicized their results in a preprint for other researchers to view. Based on the team’s observations, another group replicated the study in an independent cohort of APOEe4 carriers, mostly of European origin.  

“They found the same fibronectin variant, which confirmed our finding and gave us even more confidence in our result,” the author says.  

The two groups combined the data on their 11,000 participants, which allowed them to calculate that the mutation reduces the odds of developing Alzheimer’s in APOE4 carriers by 71% and forestalls the disease by roughly four years in those who eventually develop the disease. 

The researchers estimate that 1% to 3% of APOEe4 carriers in the United States—roughly 200,000 to 620,000 people—may also carry the protective fibronectin mutation. 

The fibronectin variant, though discovered in APOEe4 carriers, could protect against Alzheimer’s disease in people with other forms of APOE. 

“There’s a significant difference in fibronectin levels in the blood-brain barrier between cognitively healthy individuals and those with Alzheimer's disease, independent of their APOEe4 status,” the author says.  

“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.” 

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

http://sciencemission.com/site/index.php?page=news&type=view&id=publications%2Frare-genetic-variation&filter=22