These mouse models include humanized variants of the apolipoprotein E (APOE) gene (ε2, ε3, and ε4), the strongest genetic risk factor for late-onset AD in humans; humanized nitric oxide synthase 2 (hNOS2) to mimic human-like immune responses; sex (male and females); age (young and middle-aged); and environmental stressors such as high-fat diet environment [28-30]. Here, APOE is linked to Alzheimer disease.