We added additional support for the lack of single marker associations between these SNPs and amyloid deposition; however, we provide new evidence for an epistatic relationship between BIN1 x PICALM. This interaction suggests that using powerful quantitative endophenotypes derived from neuroimaging measures may be a fruitful avenue for exploring epistatic relationships among candidate genes in order to explain some of the missing heritability of AD. This evidence concerns the gene PICALM and Alzheimer disease.