Systematic druggable genome-wide Mendelian randomisation identifies therapeutic targets for Alzheimer’s disease

Alzheimer's disease (AD) is the leading cause of dementia. Currently, there are no effective disease-modifying treatments for AD. Mendelian randomisation (MR) has been widely used to repurpose licensed drugs and discover novel therapeutic targets. Thus, we aimed to identify novel therapeutic targets for AD and analyse their pathophysiological mechanisms and potential side effects.A two-sample MR integrating the identified druggable genes was performed to estimate the causal effects of blood and brain druggable expression quantitative trait loci (eQTLs) on AD. A repeat study was conducted using different blood and brain eQTL data sources to validate the identified genes. Using AD markers with available genome-wide association studies data, we evaluated the causal relationship between established AD markers to explore possible mechanisms. Finally, the potential side effects of the druggable genes for AD treatment were assessed using a phenome-wide MR.Overall, 5883 unique druggable genes were aggregated; 33 unique potential druggable genes for AD were identified in at least one dataset (brain or blood), and 5 were validated in a different dataset. Among them, three prior druggable genes (epoxide hydrolase 2 (EPHX2), SERPINB1 and SIGLEC11) reached significant levels in both blood and brain tissues. EPHX2 may mediate the pathogenesis of AD by affecting the entire hippocampal volume. Further phenome-wide MR analysis revealed no potential side effects of treatments targeting EPHX2, SERPINB1 or SIGLEC11.This study provides genetic evidence supporting the potential therapeutic benefits of targeting the three druggable genes for AD treatment, which will be useful for prioritising AD drug development.