These results have called into question the validity of using familial AD, where the pathogenesis is undoubtedly related to Ab generation, as a model for the more common sporadic AD. In particular, it is possible that the sporadic disease may have a distinct pathogenesis, perhaps based on immune dysregulation, that is not based on aberrant APP metabolism and the Foretinib c-Met inhibitor consequent production of Ab. To address this issue, we have employed an invertebrate model system that exclusively reports the toxicity of Ab; that is, a worm expressing Ab under the control of a muscle-specific driver. While, in this particular model system, the paralysis is likely to be caused by muscle damage, rather than neurodegeneration, it is known that Ab toxicity can be observed across a wide range of cell types and the mechanisms may well be conserved. The worm screen in this study has reported on worm gene transcripts that, when targeted by RNAi, modify the Ab-induced paralysis phenotype. The deployment of rol-6 as a marker of Ab expression means that we can rule out any marked artefactual loss of the expression array in response to RNAi. However, we did not measure expression levels of the Ab peptide in response to each RNAi treatment, so we cannot exclude the possibility that for a particular RNAi treatment that effects on paralysis could be attributed to changes in transgene expression rather than an effect on Ab toxicity. Furthermore this study can usefully be extended by including worm lines carrying mutant alleles of the genes implicated by the RNAi studies both in mammalian systems and in C. elegans. In this study our goal was to use the results of the worm genetic screen to detect GWAS genes with borderline significance that were nevertheless involved in the pathogenesis of sporadic AD. Our initial, and most stringent, test indicated that none of the genes in the GWAS white or grey zones were identical to the human orthologues of the 61 worm modifier genes. This negative finding suggests that, at least for the predominantly Caucasian populations in which GWAS studies have been performed, Ab toxicity cannot be considered as identical to sporadic AD. Rather the data support the idea that other pathological pathways may be important in the disorder. However, we did observe that 6 worm gene orthologues were predicted to interact physically with members of the GWAS white+grey zone gene products. It was also notable that worm modifier genes were much more likely than chance to have a human orthologue.