To address whether trisomy 21 influences AD pathogenesis, we generated a combined murine DS-AD model by crossing the 5×FAD AD model with the Dp16 DS mouse model, and immunoblot analyses confirmed an upregulation of USP25, APP, and APP-carboxy-terminal fragments (APP-CTFs) in the cortices of 5×FAD; Dp16 mice compared with that of 5×FAD mice (Supplemental Figure 1, A–F; supplemental material available online with this article; https://doi.org/10.1172/JCI152170DS1). Here, USP25 is linked to Alzheimer disease.