Genetic variant found that reduces risk of Alzheimer's

A novel genetic variant reduces the risk of Alzheimer's disease by up to 70 percent in people who are predisposed.

Researchers at Columbia University in New York investigated the genomes of healthy people with an Alzheimer's-associated gene to see if they carried another genetic variant that protected them. They discovered that many of these unaffected individuals carried a variant in the FN1 gene which allows the toxic Alzheimer's protein, amyloid, to filter out of the brain into the blood.

'We may need to start clearing amyloid much earlier and we think that can be done through the bloodstream,' said Professor Richard Mayeux, chair of the Department of Neurology at Columbia University and co-leader of the study, which was published in the journal, Acta Neuropathologica.

Individuals with two copies of the APOEe4 allele have a ten times increased risk of developing Alzheimer's disease. However, some people appear to be immune to the effects of APOEe4. Dr Badri Vardajaran, assistant professor of neurological science at Columbia University and second co-leader of the study, said 'We hypothesised that these resilient people may have genetic variants that protect them.'

The research team sequenced the entire genomes of elderly, cognitively healthy individuals with two APOEe4 copies – one from each parent – to identify other common genetic variants that may confer protection against Alzheimer's disease.

Among 3578 individuals over the age of 70, they identified 510 common genetic variants. A particular variant in FN1, which encodes for a protein called fibronectin, was prioritised due to the role it plays in the blood brain barrier – which controls what enters and leaves the brain tissue.

Upon examining postmortem human brain tissue, Dr Caghan Kizil, assistant professor of neurological science at Columbia University and final co-leader of the study, said '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.'

'It made us think that excess fibronectin could be preventing the clearance of amyloid deposits from the brain,' added Dr Kizil. The team confirmed their hypothesis in a zebrafish model of Alzheimer's disease – those with lower levels of fibronectin had reduced pathology.

The team estimate that the FN1 variant reduces the risk of Alzheimer's disease in APOEe4 carriers by up to 70 percent. They also predict that one to three percent of APOEe4 carriers in the USA may have the FN1 variant – which equates to 200,000 to 620,000 people.

Dr Kizil said, '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.'