Alzheimer's disease risk gene Wwox controls amyloid pathology through metabolic reprogramming

Genome-wide association studies have identified multiple loci that contribute to late-onset Alzheimer's disease risk, yet the functional mechanisms of many candidate genes remain unclear. WW-domain containing oxidoreductase (WWOX) is one such gene associated with disease and downregulated in patient brains, but its role in neurodegeneration is poorly understood. Here, we use Drosophila models to investigate the cell-type-specific and mechanistic roles of Wwox in ageing and amyloid-β₄₂ (Aβ₄₂)-induced pathology. Neuronal and glial knockdown of Wwox reduced lifespan and increased sleep drive, indicating a role in brain homeostasis. In an Aβ₄₂ transgenic model, neuronal Wwox knockdown exacerbated toxicity, shortening lifespan, impairing locomotion, and increasing soluble Aβ₄₂ levels. Transcriptomic and metabolomic analyses revealed that Wwox knockdown in an Aβ₄₂ transgenic model promotes metabolic reprogramming, characterized by elevated lactate dehydrogenase (Ldh) expression and increased lactate levels, driven by activation of the stress-responsive transcription factor Atf4. Genetic reduction of Ldh rescued locomotor deficits, identifying dysregulated pyruvate metabolism as a key mediator of Wwox-dependent neurotoxicity. Conversely, overexpression of Wwox in neurons markedly reduced amyloid burden, improved survival and locomotor function, and reversed Aβ₄₂-induced transcriptional changes. Both Aβ₄₂ and the protective effects of Wwox were associated with altered amino acid metabolism, including changes in the cysteine and L-methionine pathway. Together, these findings identify WWOX as a regulator of neuronal metabolic state, linking genetic risk to amyloid pathology via metabolic reprogramming, and highlight WWOX activation as a potential therapeutic strategy in Alzheimer's disease.