Explainable hierarchical machine-learning approaches for multimodal prediction of conversion from mild cognitive impairment to Alzheimer's disease.

Alzheimer's disease (AD) is a neurodegenerative disorder that challenges early diagnosis and intervention, yet the black-box nature of many predictive models limits clinical adoption. In this study, we developed an advanced machine learning (ML) framework that integrates hierarchical feature selection with multiple classifiers to predict progression from mild cognitive impairment (MCI) to AD. Using baseline data from 580 participants in the Alzheimer's Disease Neuroimaging Initiative (ADNI), categorized into stable MCI (sMCI) and progressive MCI (pMCI) subgroups, we analyzed features both individually and across seven key groups. The neuropsychological test group exhibited the highest predictive power, with several of the top individual predictors drawn from this domain. Hierarchical feature selection combining initial statistical filtering and machine learning based refinement, narrowed the feature set to the eight most informative variables. To demystify model decisions, we applied SHAP-based (SHapley Additive exPlanations) explainability analysis, quantifying each feature's contribution to conversion risk. The explainable random forest classifier, optimized on these selected features, achieved 83.79% accuracy (84.93% sensitivity, 83.32% specificity), outperforming other methods and revealing hippocampal volume, delayed memory recall (LDELTOTAL), and Functional Activities Questionnaire (FAQ) scores as the top drivers of conversion. These results underscore the effectiveness of combining diverse data sources with advanced ML models, and demonstrate that transparent, SHAP-driven insights align with known AD biomarkers, transforming our model from a predictive black box into a clinically actionable tool for early diagnosis and patient stratification.