New Genetic Variant May Guard Against Alzheimer's

A new genetic variant in individuals who are APOE4 carriers is linked to a 70% reduction in the risk for Alzheimer's disease (AD), new research suggested.

The variant occurs on the fibronectin 1 (FN1) gene, which expresses fibronectin, an adhesive glycoprotein that lines the blood vessels at the blood-brain barrier and controls substances that move in and out of the brain.

While fibronectin is normally present in the blood-brain barrier in small amounts, individuals with AD tend to have it in excess. Normally, patients with AD have amyloid deposits that collect in the brain, but those with the FN1 variant appear to have the ability to amyloid from the brain before symptoms begin.

The researchers estimate that 1%-3% of APOE4 carriers in the United States — roughly 200,000-620,000 people — may have the protective mutation.

"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," Caghan Kizil, PhD, of Columbia University Vagelos College of Physicians and Surgeons in New York City, and a co-leader of the study, said in a press release.

The findings were published online on April 10 in Acta Neuropathologica.

Combing Genetic Data

To find potentially protective AD variants, the investigators sequenced the genomes of more than 3500 APOE4 carriers older than 70 years with and without AD from various ethnic backgrounds.

They identified two variants on the FN1 gene, rs116558455 and rs140926439, present in healthy APOE4 carriers, that protected the APOE4 carriers against AD.

After Kizil and colleagues published their findings in a preprint, another research group that included investigators from Stanford and Washington Universities replicated the Columbia results in an independent sample of more than 7000 APOE4 carriers aged 60 years who were of European descent and identified the same FN1 variant.

The two research groups then combined their data on 11,000 participants and found that the FN1 variant rs140926439 was associated with a significantly reduced risk for AD in APOE4 carriers (odds ratio, 0.29; P = .014). A secondary analysis showed that the variant delayed AD symptom onset by 3.4 years (P = .025).

The investigators hope to use these findings to develop therapies to protect APOE4 carriers against AD.

"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," Kizil said.

Study limitations included a lack of longitudinal data on the relationship between amyloid concentration and fibronectin and the fact that investigators conducted the studies in clinically assessed individuals. Given the rare occurrence of the FN1 mutation, researchers do not have neuropathological assessments of study participants with the variant.

The study was funded by the National Institute on Aging, the Schaefer Research Scholars Program Award, Taub Institute Grants for Emerging Research, the National Institute of General Medical Sciences, and the Thompson Family Foundation Program for Accelerated Medicine Exploration in Alzheimer's Disease and Related Disorders of the Nervous System. There were no disclosures reported.