Exposome-wide association study and predictive risk score for incident Alzheimer's disease and related dementias.

INTRODUCTION: Environmental exposures contribute substantially to Alzheimer's disease and related dementias (ADRD), yet comprehensive exposome-wide investigations systematically evaluating multi-domain environmental factors remain limited and lacking utility for precision medicine. METHODS: We conducted an exposome-wide association study (ExWAS) among 499,992 UK Biobank participants, examining 193 exposures across five domains (social, physical, chemical, lifestyle, and ecosystems). Cox proportional hazard models with Bonferroni correction identified ADRD-associated exposures. We used the XGBoost classifier to build a predictive model and further developed an exposomic risk score (ERS) for risk stratification. RESULTS: During a 15.3-year median follow-up, 8881 participants (1.77%) developed ADRD, including 4000 with Alzheimer's disease. ExWAS identified 76 exposures after Bonferroni correction. The prediction model achieved area under the curve (AUC) = 0.718, outperforming demographics+apolipoprotein E (APOE) status alone (AUC = 0.678). The ERS stratified ADRD risk (highest vs lowest quartile hazard ratio [HR] = 2.97, 95% confidence interval [CI]: 2.59-3.41). DISCUSSION: The ERS has the potential to contribute to clinically relevant prevention strategies for ADRD.