Fig. 1: Cross-species dissection of Alzheimer’s disease (AD) pathologic triggers.

A Hypothetical causal chain linking AD triggers, either directly or indirectly, to gene expression perturbations, and Alzheimer’s disease pathophysiology. Perturbations in gene expression that are causal modifiers of disease pathophysiology may be either amplifying or protective. Amplifying changes are pathogenic, promoting AD pathogenesis; whereas protective changes are compensatory, attenuating AD progression. B Control and AD transgenic models (n = 3 for each genotype) were profiled for locomotor behavior and gene expression using RNA-sequencing from Drosophila heads, including up to 9 timepoints between 2 and 57 days. AD model genotypes were as follows: Aβ (elav-Gal4/+; UAS-Aβ/+) and tau (elav-Gal4/+; UAS-tau/+). Both wildtype (w¹¹¹⁸) and driver (elav-GAL4/+) controls were evaluated. See also Supplementary Fig. 1. C Venn diagram highlighting shared and unique differentially expressed genes following pan-neuronal expression of Aβ or tau. Linear regression was performed comparing elav > Aβ or elav>tau with elav-GAL4 driver controls, including longitudinal data (days 2–28 for Aβ and days 2–42 for tau) and adjusting for age. Statistical analysis was based on a Wald test (false discovery rate (FDR) < 0.5). See also Supplementary Fig. 1B and Supplementary Table 2. D Plots highlight shared and unique pathways perturbed in Aβ and tau transgenic flies, based on gene ontology term enrichment. Statistical analysis based on the hypergeometric overlap test (FDR < 0.5). E Cross-species analysis highlights genes within human AD-associated coexpression modules, for which expression of conserved Drosophila homologs are triggered by Aβ (green), tau (purple), or both (yellow). Each bar indicates the total module size, based on the total number of conserved genes. Purple asterisks indicate significant enrichment for tau differentially-expressed genes; black asterisks indicate enrichment for both tau and Aβ DEGs. See also Supplementary Table 5. F Cross-species analysis highlights genes within human coexpression modules, for which Drosophila homologs are differentially expressed in response to AD and related dementia pathologic triggers (blue: Aβ, tau, or alpha-synuclein), aging (orange), or both (yellow). See also Supplementary Fig. 1C, D. (E-F) Module names incorporate abbreviations denoting the relevant brain regions: CBE, cerebellum; TCX, temporal cortex; FP, frontal pole; IFG, inferior frontal gyrus; PHG, parahippocampal gyrus; STG, superior temporal gyurs; and DLPFC, dorsolateral prefrontal cortex.