(A) The additional Hsa21 gene content in Tc1 (yellow), in the Dp(10)2Yey (orange), Dp(17)3Yey (light grey) and Dp3Tyb (red) segmental duplication models of DS as shown. The number of additional human genes in the Tc1, and the additional number of mouse genes in the Dp(10)2Yey, Dp(17)3Yey and Dp3Tyb as listed. These lines were crossed with the AppNL-F mouse model of amyloid-β accumulation (blue), to generate Tc1;AppNL-F(green), Dp(10)2Yey;AppNL-F (brown), Dp(17)3Yey;AppNL-F(dark grey), and Dp3Tyb-AppNL-F (purple) offspring, homozygous for the AppNL-F allele and carrying the additional gene content. The location of APP/App is indicated by the blue line, this locus is altered in the AppNL-F model such that the amyloid-β sequence is humanised and the model carries the AD-causal Swedish (NL) and Iberian (F) mutations. This colour scheme is used in subsequent figures to code for each of the mouse models. (B) Schematic of the generation of experimental cohorts for the duplication models (Dp(10)2Yey, Dp(17)3Yey and Dp3Tyb) used in the studies, experimental cohorts were produced by crossing Dpx;AppNL-F/+ mice with AppNL-F/+ mice.