APOE and Alzheimer disease: To gain insight into the early molecular changes associated with the pathophysiology of AD, two mutants from the same C57BL/6 background at 3 months were included: an early-onset AD (EOAD) model (5xFAD) that overexpresses mutant human amyloid-beta precursor protein and human presenilin 1 harboring multiple AD-associated mutations16; and a late-onset AD (LOAD) model (APOE*4/Trem2*R47H) that carries two of the highest risk factor mutations of LOAD, including a humanized ApoE knock-in allele and missense mutations in the mouse Trem2 gene17,18.