November 4, 2013

New Genes Tied to Alzheimer’s Disease

Senior men playing chess

Researchers identified 11 new genes that affect the risk for Alzheimer’s disease. The findings point to novel targets for preventing or delaying the disease.

Alzheimer’s disease is the most common cause of dementia in older adults. It affects more than 5 million Americans. A hallmark of the disease is the abnormal accumulation of amyloid protein in the brain. Until 2009, variants in only one gene, APOE, had been identified as a risk factor for late-onset Alzheimer's disease, the most common form of the disorder. The list of known genetic risk factors has since grown to include several others.

Large-scale analyses are needed to gain the statistical power to identify additional genetic risk factors. Scientists in the International Genomic Alzheimer’s Project (IGAP) have been working together since 2011 on genome-wide association studies (GWAS), which involve thousands of DNA samples and shared datasets. GWAS are aimed at detecting subtle genetic differences that are statistically associated with disease.

IGAP’s latest effort involved scanning the DNA of more than 74,000 older volunteers from 15 countries. Participants included people with late-onset Alzheimer's disease and those free of the disorder. It’s the largest genetic analysis yet conducted in Alzheimer's research. The work was supported in part by NIH’s National Institute on Aging (NIA) and other NIH components. The findings were reported online in Nature Genetics on October 27, 2013.

The scientists confirmed many of the previously identified genes associated with the onset and progression of late-onset Alzheimer’s. In addition, they identified 11 new genes associated with the disease: HLA-DRB5/HLA-DRB1, SORL1, PTK2B, SLC24A4/RIN3, ZCWPW1, CELF1, NME8, FERMT2, CASS4, INPP5D, and MEF2C. The study also highlighted another 13 variants that merit further analysis.

The findings strengthen evidence about the involvement of certain pathways in Alzheimer’s disease, including the immune response, inflammation, cellular protein trafficking, and lipid transport. They also add to evidence for other pathways that may influence disease development, including synapse function, cytoskeletal function, and specialized cells in the brain called microglia.

“Interestingly, we found that several of these newly identified genes are implicated in a number of pathways,” says Dr. Gerard Schellenberg of the University of Pennsylvania School of Medicine, who directs one of the major IGAP consortia. “Alzheimer’s is a complex disorder, and more study is needed to determine the relative role each of these genetic factors may play.”

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References: Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer's disease. Nat Genet. 2013 Oct 27. doi: 10.1038/ng.2802. [Epub ahead of print]. PMID: 24162737.

Funding: NIH’s National Institute on Aging (NIA), National Heart, Lung, and Blood Institute (NHLBI), National Institute of Neurological Disorders and Stroke (NINDS), and other NIH components; the Cohorts for Heart and Aging Research in Genomic Epidemiology; the European Alzheimer's Disease Initiative; Genetic and Environmental Research in Alzheimer's Disease (GERAD); the Alzheimer's Association; and an extensive number of international governmental, private, and public research groups.