The association between the apolipoprotein E (APOE [OMIM 107741]) gene and Alzheimer disease (AD) has been known for longer than 25 years1,2 and has remained the strongest and most consistent association between AD risk and a common DNA variant.3,4 Dozens of genetic loci are associated with risk of AD, and hundreds of variants across 3 genes (APP [OMIM 605714], PSEN1 [OMIM 104311], and PSEN2 [OMIM 600759]) are known to cause early-onset, autosomal dominant forms of AD.4,5,6 This genetic heterogeneity has also been observed at the APOE locus. This evidence concerns the gene APOE and early-onset autosomal dominant Alzheimer disease.