Genetic Variant Appears to Protect Against Alzheimer Disease in At-Risk Individuals
A genetic variant may decrease the odds of developing Alzheimer disease (AD) by as much as 70% in people who carry the APOE ε4 allele, which is known to significantly increase AD risk. Researchers published the findings online in Acta Neuropathologica.
The protective variant, located in the gene that makes fibronectin, appears to protect against AD by allowing toxic forms of amyloid through the blood-brain barrier and out of the brain.
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“Alzheimer 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,” said researcher Caghan Kizil, PhD, associate professor of neurological sciences at the Columbia University Vagelos College of Physicians and Surgeons, New York, New York. “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.”
To find potentially protective genetic mutations in APOE ε4 carriers, Columbia University researchers analyzed whole-genome sequencing data for hundreds of carriers, with and without AD, who were older than 70 years and from various ethnic backgrounds. After they identified the fibronectin variant, investigators shared the finding with other researchers in a preprint server. Teams from Stanford and Washington Universities then replicated the finding in an independent cohort of APOE ε4 carriers, most of whom were of European origin.
When the research teams combined their data, which spanned a total 11,000 participants, they calculated that the fibronectin variant in APOE ε4 carriers cut the odds of developing AD by 71%. In those who went on to develop AD, it delayed onset by 3.37 years.
The findings were validated in a zebrafish model of AD that showed reducing fibronectin increased amyloid clearance and improved other damage caused by AD. Studies in mice are underway.
Even though the study focused on APOE ε4 carriers, researchers believe the fibronectin variant could protect against AD in people who carry other forms of APOE as well.
“There’s a significant difference in fibronectin levels in the blood-brain barrier between cognitively healthy individuals and those with Alzheimer disease, independent of their APOE ε4 status,” said Dr Kizil. “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.”
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