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To access publisher's full text version of this article. Please click on the hyperlink in Additional Links field. BACKGROUND: Sequence variants, including the ε4 allele of apolipoprotein E, have been associated with the risk of the common late-onset form of Alzheimer's disease. Few rare variants affecting the risk of late-onset Alzheimer's disease have been found. METHODS: We obtained the genome sequences of 2261 Icelanders and identified sequence variants that were likely to affect protein function. We imputed these variants into the genomes of patients with Alzheimer's disease and control participants and then tested for an association with Alzheimer's disease. We performed replication tests using case-control series from the United States, Norway, The Netherlands, and Germany. We also tested for a genetic association with cognitive function in a population of unaffected elderly persons. RESULTS: A rare missense mutation (rs75932628-T) in the gene encoding the triggering receptor expressed on myeloid cells 2 (TREM2), which was predicted to result in an R47H substitution, was found to confer a significant risk of Alzheimer's disease in Iceland (odds ratio, 2.92; 95% confidence interval [CI], 2.09 to 4.09; P=3.42×10(-10)). The mutation had a frequency of 0.46% in controls 85 years of age or older. We observed the association in additional sample sets (odds ratio, 2.90; 95% CI, 2.16 to 3.91; P=2.1×10(-12) in combined discovery and replication samples). We also found that carriers of rs75932628-T between the ages of 80 and 100 years without Alzheimer's disease had poorer cognitive function than noncarriers (P=0.003). CONCLUSIONS: Our findings strongly implicate variant TREM2 in the pathogenesis of Alzheimer's disease. Given the reported antiinflammatory role of TREM2 in the brain, the R47H substitution may lead to an increased predisposition to Alzheimer's disease through impaired containment of inflammatory processes. (Funded by the National Institute on Aging and others.). Research Council of Norway National Institute on Aging P50-AG025688 U01AG006781 South-Eastern Norway Health Authority National Institutes of Health U01HG004438 National Human Genome Research Institute U01HG004610 eMERGE Administrative Coordinating Center U01HG004603 National Center for Biotechnology Information Erasmus Medical Center Erasmus University, Rotterdam Netherlands Organization for Health Research and Development Research Institute for Diseases in the Elderly Ministry of Education, Culture and Science Ministry for Health, Welfare and Sports Municipality of Rotterdam Research Institute for Diseases in the Elderly 014-93-015 Stichting Alzheimer Onder-zoek Hersenstichting Nederland Netherlands Genomics Initiative-Netherlands Organization for Scientific Research (Center for Medical Systems Biology and the Netherlands Consortium for Healthy Aging) info:eu-repo/grantAgreement/EC/FP7/201413