Novel Alzheimers Genes Unique to Ashkenazi Jews?

New research has uncovered several novel genetic risk factors for Alzheimer’s disease (AD) that may be unique to Ashkenazi Jews.

Investigators conducted a genome-wide association study (GWAS) for AD in more than 40,000 individuals drawn from more than 35 cohorts that included non-Hispanic people of European ancestry and Spanish people.

They focused specifically on 3500 individuals of almost exclusively Ashkenazi Jewish ancestry. Roughly half the sample were people with AD, and the other half were cognitively normal.

In addition to the previously established apolipoprotein E (APOE) and TREM2 genes, investigators found that Ashkenazi Jews also had several novel genetic variants potentially associated with AD: RAB3B, SMAP2, ZNF890P, SPOCK3, and GIPR.

“In a sample of Ashkenazi Jews — ie, Jews whose immediate ancestors lived in Eastern Europe — we identified association of risk for AD with variants in multiple genes, including some previously known and several novel ones that are strong biological candidates,” study investigator Lindsay Farrer, PhD, chief of biomedical genetics, Boston University Chobanian and Avedisian School of Medicine, Massachusetts, told Medscape Medical News.

Although “there are no practical implications from our study that would directly affect the diagnosis, prognosis, or treatment of Ashkenazi Jews, this study has expanded our knowledge of the genetic architecture and consequently biological pathways leading to AD,” he said.

The study was published online June 1 in Alzheimer’s & Dementia.

Founder Population

“Studies of small samples from founder populations — ie, 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,” Farrer said.

“For many centuries, Ashkenazi Jews lived in communities in Eastern Europe and were genetically isolated from their non-Jewish neighbors,” he continued.

Some rare autosomal 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 (eg, early onset breast cancer and multiple gastrointestinal cancers) “are found predominantly or at a much higher frequency in Ashkenazi Jews compared to other populations,” he said.

The investigators hypothesized that some AD susceptibility variants may be much more frequent, and more likely to show statistically significant associations, in an Ashkenazi Jewish cohort compared with more heterogenous groups with general European ancestry.

For the study they conducted a GWAS of AD in a group of Ashkenazi Jews drawn from large EA cohorts of AD cases and controls, including 35 cohorts of people with non-Hispanic European ancestry and a cohort of Spanish individuals (n = 35,273 and  n = 7409, respectively).

Whole-genome sequencing (WGS, n = 16,815) and whole-exome sequencing (WES, n = 20,504) datasets were included. A GWAS dataset of Ashkenazi Jews (n = 3096) was used as a reference panel for clustering parents. These individuals’ grandparents were all Ashkenazi Jews.

The GW and exome-wide (EW) datasets were created by combining the AD datasets according to the type of variants they contained. In particular, the GW dataset included Ashkenazi Jews in the GWAS and WGS datasets, and the EW dataset included Ashkenazi Jews in all three datasets and variants drawn from exome capture.

Gene-based analyses were conducted using aggregated rare variants.

Novel Therapeutic Targets?

The GW analyses (1355 cases and 1661 controls) revealed several significant genetic associations with AD, in addition to APOE (Table 1).

Table 1. Significant Genetic Associations With AD

Gene P value
TREM2 R47H 9.66 x 10-9
rs541586606 near RAB3B 5.01 x 10-8
rs760573036 between SPOCK3 and ANXA10 6.32 x 10-8

In the EW analyses (1504 cases and 2047 controls), study-wide significant associations were also found with rs1003710 near SMAP2 (P = 1.91 x 10-7). Additionally, a significant gene-based association was found with GIPR (P = 7.34 x 10-7).

“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,” said Farrer.

“In such communities, disease-associated variants may be much more frequent compared to samples ascertained from large, mixed populations,” he said.

“Future studies focused on the AD-associated genes in this study may lead to the development of novel AD biomarkers and therapeutic targets that might be relevant particularly for Ashkenazi Jews,” he added.

New Pathways

Commenting for Medscape Medical News, Howard Fillit, MD, cofounder and chief science officer, Alzheimer’s Drug Discovery Foundation, said that “in the context of APOE4, the gene is so powerful that it alone has predictor value of determining the risk of people [to develop AD], and TREM2 also comes into this category” of being associated with established risk.

“But what I liked about this study is that the researchers also identified other genes “consistently significantly associated with AD in this population [Ashkenazi Jews], although I’m not sure whether what they found is specific to this population or also relates to other populations since we don’t have these types of direct comparisons,” said Fillit, who is also clinical professor of geriatric medicine and palliative care, medicine and neuroscience at Mount Sinai School of Medicine, New York City and was not involved with the study.

Given the identification of these less recognized genes, a polygenic risk score could perhaps be developed, similar to what is being developed in cardiovascular disease, said Fillit.  

The “biological plausibility” of the genes identified in this study may not specifically predict the risk of AD in Ashkenazi Jewish populations, but identifying these genes could provide “new pathways for potential genetic risk factors for the disease” and shed light on disease pathogenesis, thus laying the groundwork for the development of new medications.

This work was supported in part by grants from the National Institutes of Health. Farrer has reported no relevant financial relationships. Other funding sources and author disclosures are listed with the article. Fillit has reported no relevant financial relationships.

Alz Dem. Published online June 1, 2023. Full text

Batya Swift Yasgur, MA, LSW, is a freelance writer with a counseling practice in Teaneck, New Jersey. She is a regular contributor to numerous medical publications, including Medscape and WebMD, and is the author of several consumer-oriented health books as well as Behind the Burqa: Our Lives in Afghanistan and How We Escaped to Freedom (the memoir of two brave Afghan sisters who told her their story).

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