BACKGROUND: Homozygous loss-of-function mutations in TREM2, encoding the 
triggering receptor expressed on myeloid cells 2 protein, have previously been 
associated with an autosomal recessive form of early-onset dementia.
METHODS: We used genome, exome, and Sanger sequencing to analyze the genetic 
variability in TREM2 in a series of 1092 patients with Alzheimer's disease and 
1107 controls (the discovery set). We then performed a meta-analysis on imputed 
data for the TREM2 variant rs75932628 (predicted to cause a R47H substitution) 
from three genomewide association studies of Alzheimer's disease and tested for 
the association of the variant with disease. We genotyped the R47H variant in an 
additional 1887 cases and 4061 controls. We then assayed the expression of TREM2 
across different regions of the human brain and identified genes that are 
differentially expressed in a mouse model of Alzheimer's disease and in control 
mice.
RESULTS: We found significantly more variants in exon 2 of TREM2 in patients 
with Alzheimer's disease than in controls in the discovery set (P=0.02). There 
were 22 variant alleles in 1092 patients with Alzheimer's disease and 5 variant 
alleles in 1107 controls (P<0.001). The most commonly associated variant, 
rs75932628 (encoding R47H), showed highly significant association with 
Alzheimer's disease (P<0.001). Meta-analysis of rs75932628 genotypes imputed 
from genomewide association studies confirmed this association (P=0.002), as did 
direct genotyping of an additional series of 1887 patients with Alzheimer's 
disease and 4061 controls (P<0.001). Trem2 expression differed between control 
mice and a mouse model of Alzheimer's disease.
CONCLUSIONS: Heterozygous rare variants in TREM2 are associated with a 
significant increase in the risk of Alzheimer's disease. (Funded by Alzheimer's 
Research UK and others.).