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. 2013 Jan 10;368(2):107-16.
doi: 10.1056/NEJMoa1211103. Epub 2012 Nov 14.

Variant of TREM2 associated with the risk of Alzheimer's disease

Thorlakur Jonsson  1 , Hreinn Stefansson, Stacy Steinberg, Ingileif Jonsdottir, Palmi V Jonsson, Jon Snaedal, Sigurbjorn Bjornsson, Johanna Huttenlocher, Allan I Levey, James J Lah, Dan Rujescu, Harald Hampel, Ina Giegling, Ole A Andreassen, Knut Engedal, Ingun Ulstein, Srdjan Djurovic, Carla Ibrahim-Verbaas, Albert Hofman, M Arfan Ikram, Cornelia M van Duijn, Unnur Thorsteinsdottir, Augustine Kong, Kari Stefansson
Affiliations

Variant of TREM2 associated with the risk of Alzheimer's disease

Thorlakur Jonsson et al. N Engl J Med. .

Abstract

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.).

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Figures

Figure 1
Figure 1. Cognition as a Function of Age in Controls Who Were Carriers or Noncarriers of the rs75932628-T Variant Associated with the Risk of Alzheimer’s Disease
Shown are scores on the Cognitive Performance Scale (CPS) for carriers and noncarriers of the rs75932628-T variant associated with Alzheimer’s disease, according to age. Scores on the CPS range from 0 to 6, with higher scores indicating more severe impairment. Values are shown in 2-year bins (i.e., the data point for 81 years of age contains data for ages 80 and 81), except for the last bin, which represents ages of 98, 99, and 100 years. No CPS data were available for carriers in the last age bin. Each data point represents the average CPS score for participants in the respective age bin. The I bars represent standard errors. The graph is based on 307 measurements from 53 carriers and 24,152 measurements from 3699 noncarriers. Patients in whom Alzheimer’s disease had been diagnosed were not included in the analysis.
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