A) Mating strategy and experimental design. B) Schematic of the human PSEN2 protein (adapted from https://www.alzforum.org/mutations/psen-2 with permission from FBRI LLC (Copyright © 1996–2020 FBRI LLC. All Rights Reserved. Version 2.7 –2020)). Amino acid residues are color-coded to indicate whether substitutions have been observed to be pathogenic (orange), non-pathogenic (green) or of uncertain pathogenicity (blue). The site of the human EOfAD mutation N141I, in the second transmembrane domain (TMD) is indicated by the red single-headed arrow. The aspartate residues critical for γ-secretase catalysis are indicated by a red double-headed arrow. C) Upset plot indicating the number of differentially expressed (DE) genes in each comparison of the psen2 mutant genotypes to wild type noting that only 2 genes appear to be DE in common between both comparisons. D) Mean-difference (MD) plot and E) volcano plot of DE genes in each comparison. Note that the logFC axis limits in D) and E) are constrained to -5 and 5 for visualization purposes.

A) Heatmap showing the significant KEGG [29] gene sets in psen2 heterozygous mutant brains, clustered based on their Euclidean distance. The columns represent the gene sets which are significant in at least one comparison, and the rows are the two comparisons. The color of each cell represents the significance value with more significant gene sets appearing lighter. The numbers within each cell are the FDR-adjusted harmonic mean p-values (HMP). ns, not significant. B) Heatmap indicating the logFC of genes in the KEGG_RIBOSOME gene set in EOfAD/+ and FS/+ brains. C) Upset plot showing the overlap of leading edge genes from the fgsea algorithm in gene sets found to be altered in EOfAD-like/+ brains, and D) FS/+ brains. See the online version for color.