In fact, when variants with particularly large effects do exist—such as APOE in Alzheimer’s disease [27], BRCA1 and BRCA2 in breast and ovarian cancer [28], and LRRK2 in Parkinson’s disease [29]—previous authors have suggested simulations in lieu of their analytical approximation [13]. This evidence concerns the gene APOE and early-onset autosomal dominant Alzheimer disease.