Researchers find new Alzheimer’s genetic risk factors

Alzheimer’s disease (AD), the most common neurodegenerative disorder in the world, affects people of all ethnicities and races. Nevertheless, most genetic research on AD has been performed on individuals of European ancestry (EA), with a limited number of large-scale genetic studies in other populations.

Over the ages, Ashkenazi Jews were almost completely genetically isolated from their non-Jewish neighbors. As a result, researchers from Boston University’s Chobanian & Avedisian School of Medicine hypothesized in a study that some AD susceptibility variants are more frequent and thus more likely to show statistically significant associations in this group, compared with much larger and more genetically heterogeneous EA cohorts.

Their study recently appeared in Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association under the title “Novel loci for Alzheimer’s disease identified by a genome-wide association study in Ashkenazi Jews.”

Some rare autosomal (involving any of the 22 numbered pairs of chromosomes found in most human cells) recessive disorders manifesting in childhood – including Tay-Sachs disease, Gaucher disease, familial dysautonomia, Canavan disease, Bloom syndrome and spinal muscular atrophy – as well as particular gene mutations conferring a high risk of common disorders, such as early-onset breast cancer and multiple gastrointestinal cancers, are found predominantly or at a much higher frequency in Ashkenazi Jews, compared with other populations.

“Most Alzheimer’s disease loci have been discovered in individuals with European ancestry,” the researchers wrote.

According to Dr. Lindsay A. Farrer, chief of biomedical genetics at Boston University, “Our study illustrates the greatly increased power for detection of genetic associations in communities like

Ashkenazi Jews who trace their lineage to a relatively small group of ancestors. In such communities, disease-associated variants may be much more frequent compared to samples ascertained from large, mixed populations.”

The researchers said the study illustrated the greatly increased power for detection of genetic associations in communities such as Ashkenazi Jews, who trace their lineage to a relatively small group of ancestors.

“Some genetic association signals for complex diseases like AD are likely to be stronger in founder populations that are relatively genetically homogeneous,” Farrer said.

Trans-ethnic studies have shown that population differences in genetic background can be leveraged to make novel discoveries that might require a sample size several orders of magnitude larger to achieve similar success studying a single population, according to the study.

“Similarly, studies of small samples from founder populations (ethnic or religious groups whose origins can be traced to a limited number of ancestors and thus have a more homogeneous genetic background) have successfully detected robust and subsequently validated associations of AD with several genes,” the researchers wrote.

Farrer and his colleagues conducted a genome-wide association study for AD in a sample of 3,500 people whose ancestry was almost exclusively Ashkenazi Jewish, including roughly equal numbers of persons with AD and cognitively normal individuals who were identified in a much larger group of EA participants in large national AD genetics studies using an approach that compared genetic signatures with members of an Ashkenazi Jewish reference sample.

The researchers identified several genetic risk factors for AD, including some previously known (APOE, TREM2) and several novel ones that are strong biological candidates (RAB3, SMAP2, ZNF890P, SPOCK3, GIPR).