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Alzheimer's Disease Risk Score Developed Based on Multiple Risk Variants

NEW YORK (GenomeWeb) – An international team led by investigators in the US and Norway has developed a polygenic risk score that shows promise for predicting the development of late-onset Alzheimer's disease in a manner that's tailored to a given individual's age.

The researchers first narrowed in on potentially risky variants using genotyping profiles for 17,008 individuals with Alzheimer's disease and more than 37,000 unaffected controls participating in the International Genomics of Alzheimer's Project. From there, they developed and tested a polygenic hazard score on tens of thousands more individuals from cohorts assembled by the Alzheimer's Disease Genetics Consortium and the Alzheimer's Disease Neuroimaging Initiative.

As reported in PLOS Medicine today, the team's proposed polygenic risk score appeared to predict late-onset Alzheimer's disease development, even in individuals who did not carry the risky E4 allele of well-known Alzheimer's gene APOE. Because individuals with the most elevated risk scores typically developed the disease at a younger age, such polygenic tests may eventually provide clues for those searching for ways to prevent or treat the disease.

"We think these measures of polygenetic risk, of involving multiple genes, will be very informative for early [Alzheimer's disease] diagnosis, both in determining prognosis and as an enrichment strategy in clinical trials," co-first author Rahul Desikan, a neuroradiology researcher at the University of California, San Francisco, said in a statement.

With data for 6,409 individuals with Alzheimer's disease and nearly 9,400 unaffected controls, the researchers developed their proportional hazard model using insights from more than 1,800 Alzheimer's-associated SNPs, folding in information on Alzheimer's rates in the population to establish a risk score that takes age and genotype into account.

The resulting risk score encompassed 31 SNPs and two APOE variants. When the team took a crack at replicating the risk score in several case-control cohorts, it found that the score provided insights into risk of Alzheimer's disease in general, the timing of disease onset, and disease progression.

"[B]y integrating population-based incidence proportion and genome-wide data into a genetic epidemiology framework, we have developed a [polygenic hazard score] for quantifying the age-associated risk for developing [Alzheimer's disease]," the authors concluded. "Measures of polygenic variation may prove useful for stratifying [Alzheimer's disease] risk."

In a related study, also published in PLOS Medicine, researchers from King's College London, the National Institute on Aging, and elsewhere used metabolomic profiling to map out metabolite patterns in brain samples from deceased participants in the Baltimore Longitudinal Study of Aging.

Their analysis pointed to half a dozen unsaturated fatty acids that were found at altered levels in brain samples from 14 individuals with Alzheimer's disease, compared with samples from 14 healthy controls and 15 individuals with tau or amyloid build-up in the brain, but no reported memory deficits.