Two groups have independently identified a rare variant that is associated with susceptibility to late-onset Alzheimer's disease (LOAD), with an effect size similar to that of the ε4 risk allele of apolipoprotein E. Researchers in the Alzheimer Genetic Analysis Group (N. Engl. J. Med., published online 14 November 2012; doi:10.1056/NEJMoa1211851) nominated TREM2 as a promising candidate because homozygous loss-of-function TREM2 mutations cause Nasu-Hakola disease, a rare recessive, early-onset form of dementia with leukoencephalopathy and bone cysts. They generated exome sequence data sets and identified a TREM2 missense variant, R47H, which associated with LOAD in cohorts from North America and Europe. Separately, researchers at deCODE Genetics (N. Engl. J. Med., published online 14 November 2012; doi:10.1056/NEJMoa1211103) identified the R47H variant in an imputation-based genome-wide association study using the Icelandic population and replicated the association with LOAD in North American and European cohorts. TREM2 is an immune phagocytic receptor expressed in brain microglia. Assuming that the TREM2 risk variants impair TREM2 function, these studies suggest that reduced function of TREM2 causes reduced phagocytic clearance of amyloid proteins or cellular debris and thus impairs a protective mechanism in the brain.