The National Institutes of Health/National Institute on Aging recently awarded a $13.7 million grant to a project led by Boston University Chobanian & Avedisian School of Medicine principal investigators Lindsay Farrer, PhD, chief of biomedical genetics and distinguished professor of genetics, and Richard Sherva, PhD, assistant professor of medicine in biomedical genetics, for research using whole genome sequencing and other approaches to identify genetic factors for Alzheimer disease (AD) in Jews currently living in Israel who trace their ancestors to southern Spain and locations in the Middle East and North Africa (MENA) and Arab citizens of Israel.
“In this project, we will leverage the genetic architecture of MENA Jews and Arab citizens of Israel as well as their distinctive environmental exposures and lifestyles, to promote discovery of AD-related genes and variants,” said Farrer. “We expect that this project will identify novel targets for development of effective drugs to treat or retard processes leading to AD.”
Research has established that there is a strong genetic component to AD, but the functional variants in AD-associated genes and precise pathogenic mechanisms by which they lead to AD are largely unknown. Most discoveries of the genetic basis of AD were made by studying Caucasians of European ancestry and required samples of between 10,000 and 100,000 subjects. The new study builds upon earlier research, including by Farrer and his colleagues, demonstrating that there is an increased power of detection – requiring dramatically fewer participants – of genetic factors among communities who trace their lineage to a relatively small group of ancestors. Previous work by Farrer and his colleagues discovered several novel AD genes in Ashkenazi Jews who originated in Eastern Europe and Arabs living in the Wadi Ara region in northern Israel.
Farrer and Sherva’s study will recruit an equal number of people over age 60 who either have AD or are considered cognitively normal and will include 3,000 MENA Jews and 1,000 Arabs, all living in Israel. Participants will have blood samples taken and analyzed for DNA and biomarker studies; undergo clinical and cognitive testing; and provide a medical history and lifestyle information.
This is a five-year grant, and the research augments the national Alzheimer Disease Sequencing Project, which seeks to understand the genetic architecture of AD and related dementias, and targets diverse populations around the world.
Researchers will perform whole genome sequencing (WGS) using the DNA samples to identify all unique genetic variants and compare genomes of participants with AD to those in the control group to identify variants that confer higher risk as well as those that protect against AD. They will compare those findings with the results of similar studies on other discrete populations. Project researchers will also analyze plasma from blood samples to look for biomarkers that indicate higher levels of proteins strongly associated with AD pathology in the brain, and then compare these findings with the WGS data to identify genetic variants that influence these protein levels. They will also identify human viruses resident in the whole genome sequence data and then use machine learning methods to search for the joint effects of viruses and genetic variants on AD risk.