In our opinion, major developments in modeling the sporadic form of AD in rodents will potentially come from the incorporation of genetic variations that increase the risk of developing AD, such as the ε4 allele of apolipoprotein E (APOE) gene, or the R47H allele of the triggering receptor expressed on myeloid cells 2 (TREM2). The gene discussed is APOE; the disease is Alzheimer disease.