A triad of AD risk, consisting of age, sex, and Apolipoprotein E epsilon 4 (APOE4) genotype, the major genetic risk factor for LOAD (Tanzi and Bertram, 2001), impacts AD risk by altering bioenergetic pathways starting in midlife, a process that can span decades (Riedel et al., 2016). The gene discussed is APOE; the disease is Alzheimer disease.