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APOE-region variants linked to Alzheimer’s disease risk

JAMA Network Open
Reuters Health - 30/10/2020 - Variants within the neighboring region of the apolipoprotein E (APOE) gene are also associated with Alzheimer's disease (AD) risk, researchers suggest.

"Although the APOE E2 and E4 alleles have a strong and robust association with risk of AD, our work provides further support that other genes and variation in the region may influence AD," Dr. Elizabeth Blue of the University of Washington School of Medicine in Seattle told Reuters Health by email.

"For example, we observed a variant, rs192879175, associated with a 50% reduction in odds of having AD among subjects without either an APOE E2 or E4 allele," she said. "Unlike the common missense variants defining the APOE E2 and E4 alleles, this uncommon variant is located between genes and bears the marks of a gene regulatory variant."

"These results are motivation to shine more light on the variation lying in the shadow of APOE so that we can better understand the roles it may play in Alzheimer's disease," she said. "I think the biggest take away for clinicians is that the effect of the APOE allele varies by individual, in part because of the genetic variation inherited alongside that APOE allele and the genetic variation around the gene."

As reported in JAMA Network Open, the genetic association study involved testing more than 14,000 variants near APOE for an association with AD in 16,795 individuals of European descent. About half of participants (9,704) were affected by AD as determined by clinicians using the US National Institute of Neurological and Communicative Disorders and Stroke and Alzheimer Disease and Related Disorders Association criteria, and the rest served as controls (not affected by AD). The median age at AD onset/evaluation was 76; 60% were women.

In unadjusted models, associations with AD were found for variants rs2075650 (odds ratio, 2.59) and rs4420638 (OR, 2.77).

However, after adjustment, rs2075650 was only nominally associated with AD among the E4 homozygotes (OR, 1.33) and rs4420638 was no longer associated with AD.

As Dr. Blue indicated, a significant association was observed between rs192879175 and AD among E3 homozygotes (OR, 0.50).

The authors state, "These findings suggest that even among individuals with the same E2/E3/E4 genotype, genetic variation within the APOE neighboring region may be associated with risk of AD."

Dr. Evadnie Rampersaud, Group Lead, Genetics, Center for Applied Bioinformatics at St. Jude Children's Research Hospital in Memphis, commented in an email to Reuters Health, "One might ask whether the onset or duration till death for the patients is different as a result of carrying rare alleles in APOE alone versus APOE plus the new locus," she said. "However, we need to validate the finding in a statistical manner first before using this new single nucleotide polymorphism for screening purposes or defining clinical care."

"It has been proposed that the APOE genotypes reside on the Neanderthal genome, which has been linked to several diseases, and most recently to severe COVID-19 risk," she noted. "More exploration of the archaic genomes may help shed light on the evolution of the variants and their possible selective roles in neurodegeneration. It will be important to also understand whether this relationship exists in our ethnic groups, such as African American AD patients."

Dr. Howard Fillit, Founding Executive Director and Chief Science Officer of the Alzheimer's Drug Discovery Foundation in New York City, also commented by email, "Genetic risks have been discovered in many diseases, but it's a long way from finding an association of a genetic variant and proving causation in the disease, and it is even more difficult to translate this information into a drug."

"The investigators would have to demonstrate the biological significance of the genetic variant," he said by email. "For instance, how does the genetic variant account for the increased risk for AD? My take home message is these are interesting findings, but the implications for patients with AD, in terms of gaining a better understanding of the biology of the disease or the potential for new drugs, are a long way off."

By Marilynn Larkin

SOURCE: https://bit.ly/34IcNzJ JAMA Network Open, online October 22, 2020.

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