Functional Insights into Alzheimer’s Risk Genes via Drosophila Screening

Genome-wide association studies have identified numerous loci linked to late-onset Alzheimer’s disease (LOAD), yet the functional roles of many risk genes remain unclear. We use Drosophila to explore conserved genetic risk factors using unbiased reverse genetic screens, currently focusing on the WW-domain containing oxidoreductase (WWOX) gene. Our work reveals that Wwox impacts lifespan, sleep, and neurodegeneration-relevant phenotypes in both neuronal and glial contexts. In a fly model of amyloid beta (Aβ42) toxicity, Wwox knockdown exacerbates disease features, while its upregulation confers protection. Multi-omics approaches suggest Wwox influences key metabolic and stress response pathways. These findings highlight the utility of Drosophila for functional interrogation of conserved AD risk genes and support further investigation of WWOX as a potential therapeutic target.