Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by the presence of extracellular amyloid plaques consisting of Amyloid-beta peptide (A beta) aggregates and neurofibrillary tangles formed by aggregation of hyperphosphorylated microtubule-associated protein tau. We generated a novel invertebrate model of AD by crossing A beta 1-42 (strain CL2355) with either pro-aggregating tau (strain BR5270) or anti-aggregating tau (strain BR5271) pan-neuronal expressing transgenic Caenorhabditis elegans. The lifespan and progeny viability of the double transgenic strains were significantly decreased compared with wild type N2 (P< 0.0001). In addition, co-expression of these transgenes interfered with neurotransmitter signaling pathways, caused deficits in chemotaxis associative learning, increased protem aggregation visualized by Congo red staining, and increased neuronal loss. Global transcriptomic RNA-seq analysis revealed 248 up-and 805 down-regulated genes in N2 wild type versus Afi beta 1-42 + pro-aggregating tau animals, compared to 293 up-and 295 down-regulated genes in N2 wild type versus AJ31-42 + anti-aggregating tau animals. Gene set enrichment analysis of A beta 1-42 + pro-aggregating tau animals uncovered up-regulated annotation clusters UDP-glucur-onosyltransferase (5 genes, P< 4.2E-4), protein phosphorylation (5 genes, P< 2.60E-02), and aging (5 genes, P< 8.1E-2) while the down-regulated clusters included nematode cuticle collagen (36 genes, P< 1.5E-21).