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

Abstract 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.