Fig. 4: Integrating genetic variation with plasma metabolites and MedDiet enhances the prediction of dementia risk and cognitive status.
a, The inclusion of genetic factors improving dementia risk prediction using Cox PH model, with an additional modest enhancement when plasma metabolites also included. Time-dependent ROC curve analyses were conducted for dementia risk over both the entire follow-up period and the first 15 years of follow-up. The baseline model predictors included age, family history of dementia, education level, smoking status, history of depression or regular antidepressant use and MedDiet index. The PRS of ADRD excluded variants in the APOE region (see Methods for selection of metabolite predictors). b, Plasma metabolites among the top contributors for predicting dementia risk as quantified by the SHAP value. Feature contributions were evaluated for Cox PH model to predict overall and 15-year dementia risk, including the full list of predictors. SHAP values were calculated for each category of predictors by summing the SHAP value of all predictors in that category. Features were ranked by the SHAP value from the highest to the lowest for predicting the overall and 15-year dementia risk. c, Integration of genetic and metabolomic data enhancing cognitive status prediction within APOE4 subgroups. The heatmap displays AUCs from an RF model classifying participants in the highest versus the lowest tertile of the overall TICS score. In subgroup analyses by APOE4 carrier status, APOE4 genotype was excluded as a predictor. For all analyses, the NHS dataset (n = 4,215) was randomly divided into training (60%) and test (40%) sets; models were fitted on the training set and evaluated on the test set. All results shown are from the test set.
