INTRODUCTION: Observational studies have reported that patients with Alzheimer's disease (AD) have a greater burden of comorbidities typically associated with stress-related psychiatric disorders. However, the contribution of hereditary factors to this comorbidity remains unclear. We evaluated phenotypic associations using observational data from the UK Biobank. METHOD: Our study focused on investigating the shared risk variants and genetic etiology underlying AD and three stress-related psychiatric disorders: post-traumatic stress disorder, anxiety disorder, and major depressive disorder. By leveraging summary statistics from genome-wide association studies, we investigated global genetic correlations using linkage disequilibrium score regression, genetic covariance analysis, and high-definition likelihood. Genome-wide cross-trait analysis with association analysis based on subsets and cross-phenotype association were performed to discover genome-wide significant risk variants shared between AD and the three stress-related psychiatric disorders. RESULTS: A significant positive genetic correlation was observed between AD and major depressive disorder using linkage disequilibrium score regression (rg = 0.231
CONCLUSION: These results advance our knowledge of the shared genetic origins of comorbidities and pave the way for advancements in the diagnosis, management, and prevention of stress-related AD.