Established genetic variants associated with large effect-sizes on AD include the two APOE missense variants known as APOE4 and APOE2(10, 11) and the two TREM2 missense variants (R47H and R62H)(12–14), all of which are present with an allele frequency of greater than 0.1% in the European population. Here, APOE is linked to Alzheimer disease.