To investigate whether human APOE4 accelerates the progression of AD in the presymptomatic stage, we bred the heterozygous 5xFAD AD transgenic mice with homozygous human APOE4 (APOE4+/+; 5xFAD−/−, termed as E4‐WT mice) or human APOE3 (APOE3+/+; 5xFAD−/−, termed as E3‐WT mice) knock‐in mice to generate mice co‐expressing APOE4, APP, and PS1 genes (APOE4+/+; 5xFAD+/−, termed as E4‐AD mice) or mice co‐expressing APOE3, APP, and PS1 genes (APOE3+/+; 5xFAD+/−, termed as E3‐AD mice) (Figure 1A). Here, APOE is linked to Alzheimer disease.