Clinical OMICS

JAN-FEB 2018

Healthcare magazine for research scientists, labs, pathologists, hospitals, cancer centers, physicians and biopharma companies providing news articles, expert interviews and videos about molecular diagnostics in precision medicine

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In the Lab 34 Clinical OMICs January/February 2018 www.clinicalomics.com U sing an unusual approach that combines linkage anal- ysis, whole–genome sequencing (WGS), and biological studies, researchers have found evidence for a new genetic variant (in the gene RAB10) that may be protective against Alzheimer 's disease (AD). Scientists at Brigham Young University (BYU), led by John S. Kauwe, Ph.D., published results of the study in Genome Medicine in November. The study aims to help explain why some patients with a fam- ily history of the condition and carrying an APOE ε4 allele live long lives without showing symptoms of the disease. Kauwe is an associate professor of biology at BYU. "We did not expect to find RAB10 variants implicated," said Kauwe. But the group prioritized that gene in their study because other findings had suggested it could play a role in AD, specifically in the rate of amyloid beta produc- tion, which is thought to be a key process in progression of the disease. New evidence for how AD progresses is sorely needed. "If you look at the landscape now, variants for late–onset Alzheimer 's are spread out across inflammation, endocytosis, the immune response, and cholesterol regula- tion," said Kauwe. The new finding from the BYU team adds to a growing list of variants implicated in the development of AD or pro- tection from it. The paper also describes a potentially pow- erful new approach for uncovering functional variants in AD, which are the most attractive targets for drug discov- ery. "The goal of Alzheimer 's genetic studies is to generate drug targets," noted Gerard Schellenberg, Ph.D., principal investigator of the Alzheimer 's Disease Genetics Consor- tium, which is the largest sequencing project focused on AD. He is also head of the Penn Neurodegeneration Genomics Center at the University of Pennsylvania Perelman School of Medicine. Advanced age and carrying the APOE ε4 allele are both major risk factors for AD, but people with these characteris- tics can still live well beyond 75 without ever showing AD symptoms. In searching for protective variants, part of the challenge is how to define "resilience" said Rudolph Tanzi, Ph.D., professor of neurology at Harvard University, and director of the Genetics and Aging Research Unit at Mas- sachusetts General Hospital. His group does its studies on the brains of people who died while deemed cognitively normal, but still had a lot of the plaques and tangles that are typically in people who have died of AD. But, as he points out, those brains are "hard to come by. " The BYU team defined people as "AD resilient" if they were at least 75 years old, cognitively normal, and carried at least one APOE ε4 allele. Having one or more of those alleles, Kauwe explained, can increase a person's risk of AD by five to 12 times. The "resilient" patients were eval- uated multiple times. "They had to be normal from their first through their final cognitive assessment to be defined as resilient," Kauwe added. In this study, the researchers used a pedigree-based approach. They started by performing linkage analyses among families with a "statistical excess" of AD mortality All in the Family– NOT Researchers ID Gene Variant that Protects against Alzheimer's Disease By Malorye Allison Branca Lighthaunter / Getty Images

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