APP and Alzheimer disease: We investigated interactions between APP mutations and APOE4 in the progression of AD pathophysiology by comparing mice across four different genotypes: APPNL-G-F/NL-G-F, which harbors three knock-in mutations in the humanized Aβ region of APP (referred to here as APP-TKI; Saito et al., 2014; Sasaguri et al., 2017); ApoE4+/wt mice with a single allele of human APOE4 knocked-in (ApoE4; Foley et al., 2022); the double-mutant (DM) APPNL-G-F/NL-G-F; ApoE4+/wt mice produced by crossing these two lines; and wild-type (WT) mice, which served as controls.