Genetic InfluenceMayo Clinic researchers have found strong evidence that genes other than the well-known susceptibility risk factor APOE4 influence the risk for developing the neurodegenerative disease.

Researchers at Mayo Clinic Jacksonville studied 25 multigenerational families of individuals diagnosed with late onset Alzheimer’s disease (LOAD), the most common form of the disorder.

The scientists found that blood levels of amyloid beta (Aß) proteins associated with AD were significantly elevated compared to protein found in non-blood relatives, such as spouses.

These first-degree relatives were cognitively normal and age 65 or less — many of them too young for symptoms of LOAD to show up.

“These results indicate that genetic factors of substantial magnitude lead to significant elevations of Aß in the blood of asymptomatic, young individuals from extended LOAD families,” says the study’s lead investigator, Nilufer Ertekin-Taner, M.D., Ph.D. “This fits with our hypothesis that Aß levels rise years before development of the disorder.”

The results, which first appeared online in October of last year, will be published in the Feb. 19 issue of Neurology.

The researchers have already identified three candidate genes on chromosome 10 that is associated with LOAD, and at least one of them, the gene that produces insulin degrading enzyme (IDE), is now regarded as a prime candidate for contributing to the disease. IDE degrades both insulin and amyloid protein, and scientists hypothesize that when there is too much insulin in the brain such as due to diabetes or lower expression levels of IDE, this may lead to toxic accumulation of Aß.

“We believe that 60 percent of the risk of developing the most common form of Alzheimer’s disease is genetic, and a good part of that is APOE4. But other genes are certainly contributing, and they could provide a platform for diagnosis and therapy in the future,” says the study’s senior author, Neill Graff-Radford, M.B.B.Ch., FRCP.

Dr. Ertekin-Taner estimates that the impact of these three genes could be as large as APOE4, which is a variant of the APOE gene that has been linked to LOAD. “Between 30 percent and 70 percent of AD can be attributable to APOE, and we estimate this locus of three genes on chromosome 10 could be as important,” she says. “The effect of the chromosome 10 locus could be due to multiple genes, with each gene having a smaller effect size than that of APOE.”

This study represents a decade of work by the Mayo researchers, who have been instrumental in discovering that one form of Aß known as Aß42 is much more toxic than the other common form of Aß, which is Aß40. They have also demonstrated that as AD progresses, Aß42 levels that have been rising for years begin to decline, presumably because more and more of the protein is being deposited within the brain.

Source: Mayo Clinic