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July 12, 2013

Consortium Discovers New Genetic Markers for Rate of Cognitive Decline in Alzheimer's Disease

Boston - An international collaborative research effort has identified a gene that may help to explain why some Alzheimer's disease patients experience a more rapid cognitive decline than others.  The study, the first genome-wide association study to examine rate of cognitive decline in Alzheimer's patients, was carried out by researchers from U.S. and European institutions as part of the Genetic Architecture of Rate of Alzheimer's Decline Consortium (GENAROAD).   New results from this study will be presented on July 17 at the Alzheimer's Association International Conference (AAIC) in Boston.


"The future of genetics research will require collaboration with large interdisciplinary teams and the GENAROAD Consortium is an excellent example of that," said Robert C. Green, MD, MPH, senior author on these studies, a leader of the Consortium and a medical geneticist at Brigham and Women's Hospital and Harvard Medical School. "We are leveraging and combining large amounts of data that have already been collected from many studies to make new discoveries that we hope will identify previously unsuspected targets for prevention and treatment."


Researchers have made progress detecting certain risk factors for Alzheimer's disease, but have not been able to explain why Alzheimer's patients decline at different rates. Green recognized the possibility of a genetic explanation for differing cognitive decline rates after directing a large treatment trial that showed enormous variability in rate of decline among participants, even after screening out individuals with vascular disease and other known medical conditions that could influence cognition. Initial findings from the GENAROAD Consortium (based on 626 individuals) were published in the March, 2013 issue of Alzheimer's & Dementia.  On July 17, researchers will announce that these initial findings have been confirmed and extended with research on more than 3,600 individuals.


"By studying the genetics of rate of cognitive decline among Alzheimer's disease cases, we were able to identify previously unsuspected variants in SPON1, a gene that has both strong statistical association with the trait and several biological functions related to Alzheimer's," said Richard Sherva, PhD, of the Boston University School of Medicine Biomedical Genetics Program, who will present the findings at the AAIC presentation and was lead author on the Alzheimer's & Dementia paper.


The spondin 1 gene, or SPON1, is not one of the genes that had been previously linked to the risk of developing Alzheimer's. To locate it, researchers scanned millions of markers across complete sets of DNA in a group of Alzheimer's patients experiencing both slow and fast rates of cognitive decline, in hopes of finding new genetic variations. This required DNA samples from a large sample of Alzheimer's patients and measurements of each individual's cognitive abilities over time as the disease progressed.


"Although we still have other cohorts that we intend to analyze, we have already identified several genes and chromosomal regions with variants that appear to significantly affect rate of decline in consistent ways across multiple cohorts," Sherva said. "A few of these genes have functions specific to neurons. Perhaps equally interesting is that we have not consistently implicated any of the approximately 20 genes that have been consistently shown to affect the risk of developing Alzheimer's disease. This indicates that a different set of genes may determine disease risk versus rate of decline."


Green said, "The discovery of SPON1 as a gene that influences rate of progression in Alzheimer's disease could go a long way toward improving our understanding of why people decline rapidly in Alzheimer's, but the work is far from complete.  As with all genome-wide association studies, replication of the initial findings with larger numbers is very important. We are continuing to add investigators and datasets with the goal of having more than 10,000 individuals to analyze over the coming year."


The GENAROAD Consortium was established in 2012, has rapidly expanded, and currently includes datasets from around the world and from several pharmaceutical companies, as well as investigators from Harvard University, Boston University, University of Washington, Rush University, Johns Hopkins University, Brigham Young University, Indiana University School of Medicine, King's College London, Cardiff University and Lille University in France. No other studies have examined a genetic basis for the varying rates of cognitive decline in Alzheimer's disease patients in an unbiased way, and GENAROAD endeavors to collect, collate, and analyze previously collected data from around the world, in order to accelerate the discovery of biological pathways involved in Alzheimer's disease.  This research could eventually provide clues to new therapies.