11 new genes that affect the risk for Alzheimer’s disease
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.
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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.”
Methylation Tied to Alzheimer’s
People with the neurodegenerative disease are more likely to have certain epigenetic patterns than those without.
In searching for epigenomic variations in people with and without Alzheimer’s disease, two groups have zeroed in on several genes at which methylation states correlate with having had the neurodegenerative disease. “The results are compelling and consistent across four cohorts of patients taken across the two studies,” Jonathan Mill of the University of Exeter who participated in both research projects, told New Scientist.
The results were published in two papers in Nature Neuroscience this week (August 17). In one study, the researchers analyzed genomic methylation patterns in the autopsied brains of 708 people; the other study looked at methylation patterns in brain samples from 122 deceased donors. Some of the participants had Alzheimer’s, others did not.
Several genes popped out as having different methylation states among the donors with Alzheimer’s. Among the few that overlapped in both studies was ANK1, a gene involved in the structure of the cell membrane. “This innovative research has discovered a potential new mechanism involved in Alzheimer’s by linking the ANK1 gene to the disease,” Simon Ridley, head of research at Alzheimer’s Research UK, which funded the studies in part, told New Scientist.
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