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.).