New Genetic Susceptibility Factors for Alzheimer’s Disease Discovered

Posted on: October 29, 2013 Topics: biostatistics, epidemiology

The largest international study ever conducted on Alzheimer’s disease, the I-GAP (International Genomics Alzheimer’s Project) consortium, has identified 11 new regions of the genome involved in the onset of this neurodegenerative disease.

The study, published in Nature Genetics, gives an overview of the molecular mechanisms underlying the disease, in an attempt to foster a better understanding of the pathophysiology of Alzheimer’s disease (AD).

Co-authors of the study include Dr. Sudha Seshadri, professor of neurology at the BU School of Medicine, who is a senior investigator in the Framingham Heart Study; Anita L. DeStefano, professor of biostatistics at the BU School of Public Health; Lindsay A. Farrer, professor of biostatistics and epidemiology at BUSPH who also is a professor of medicine, neurology, ophthalmology, genetics and genomics; and Kathryn Lunetta, professor of biostatistics.

“This study clearly demonstrates that there really is strength in numbers to identify genes that individually have a small effect on risk of Alzheimer’s,” said Farrer. “But it’s not the magnitude of the odds ratio that’s really important. Each gene we implicate in the disease process adds new knowledge to our understanding of disease mechanism and provides insight into developing new therapeutic approaches.”

Since 2009, 10 genes for Alzheimer’s disease have been identified. However, much of the individual susceptibility for developing the disease remains unexplained. So in 2011, the leaders of the four largest international research consortia on the genetics of AD joined forces to accelerate the discovery of new genes.

Supported in part by the National Institute on Aging and other components of the National Institutes of Health, in less than three years, the IGAP program has identified more genes than had been identified over the previous 20 years. The group collected genetic data on 74,076 patients and controls from 15 countries and was able to discover 11 new genes, in addition to those already known, and to target 13 other genes, yet to be validated.

The research team said the 11 new confirmed genes may open new avenues to understanding the causes of AD. For example, one of the most significant associations was found in the region known as “HLA-DRB5/DRB1” major histocompatibility complex. This finding strongly suggests the involvement of the immune system in AD. This same region has been associated with two other neurodegenerative diseases.

Some of the newly associated genes confirm biological pathways already known to be involved in AD.

The study demonstrates that a global collaboration of research efforts is effective is uncovering the mechanisms of Alzheimer’s disease, the authors said. The four founding partners in the international consortium are the Alzheimer’s Disease Genetics Consortium (ADGC), the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE), the European Alzheimer Disease Initiative (EADI) and the Genetic and Environmental Research in Alzheimer Disease (GERAD) consortium.

A number of researchers from the BU medical campus and the Framingham Heart Study are involved in the effort. Farrer co-directs the data analysis effort for the ADGC, which includes nearly all of the nation’s researchers working on the genetics of AD, as well as many investigators and resources of the 29 NIA-funded Alzheimer Disease Centers.

“This landmark international effort has uncovered new pathways — and new genes in old pathways — that are definitely associated with Alzheimer dementia,” Seshadri said. “But we need to do much work to better understand how exactly these genes work in health and disease, and to perhaps make drugs from these genes and molecules.

“We will continue to mine these results for new insights, even as we include more patients and use new technologies like whole genome sequencing to find more new pathways and genes,” she added.