Adapted from the Mayo Clinic - Jacksonville
Through one of the largest studies yet of Alzheimer's disease (AD) patients and their brothers, sisters, and children, researchers at Mayo Clinic Jacksonville have found strong evidence that genes other than the well-known susceptibility risk factor APOE4 influence who is at risk for developing the neurodegenerative disease later in life.
Studying 25 multigenerational families of individuals diagnosed with late-onset Alzheimer's disease, the most common form of the disorder, as well as hundreds of other participants, the research team found that blood levels of amyloid beta 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 late-onset Alzheimer's disease to show up.
"These results indicate that genetic factors of substantial magnitude lead to significant elevations of amyloid beta in the blood of asymptomatic, young individuals from extended late-onset Alzheimer's disease families," says the study's lead investigator, Nilufer Ertekin-Taner, M.D., Ph.D. "This fits with our hypothesis that amyloid beta levels rise years before development of the disorder."
The results, which first appeared online in October of last year, will be published in the February 19 issue of Neurology.
The researchers have already identified three candidate genes on chromosome 10 that is associated with late-onset Alzheimer's disease, 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 amyloid beta.
"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 late-onset Alzheimer's disease. "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 late-onset Alzheimer's disease."
The results also suggest that "it is conceivable that plasma amyloid beta, along with other information such as genetic variants, neuroimaging and cognitive test results, may be used in the future to identify individuals at risk for developing AD, before the onset of disease symptoms," Dr. Ertekin-Taner says.