To investigate how the interaction of ApoE4 and sex contributes to cognitive impairment and to BACE1-dependent amyloidogenesis, as well as to identify possible mechanisms underlying this interaction, we compared behavioral and molecular measures in an AD mouse model carrying the human ApoE4 allele plus triple transgenes with FAD mutations (PS1M146V, APPSwe, and tauP301L; 3xTg). Here, BACE1 is linked to Alzheimer disease.