Abstract
BACKGROUND: Mild cognitive impairment (MCI)/Alzheimer's disease (AD) is associated with cognitive decline beyond normal aging and linked to the alterations of brain volume quantified by magnetic resonance imaging (MRI) and amyloid-beta (Aβ) quantified by positron emission tomography (PET). Yet, the complex relationships between these regional imaging measures and cognition in MCI/AD remain unclear. Explainable artificial intelligence (AI) may uncover such relationships. METHOD: We integrate the AI-based deep learning neural network and Shapley additive explanations (SHAP) approaches and introduce the Deep-SHAP method to investigate the multivariate relationships between regional imaging measures and cognition. After validating this approach on simulated data, we apply it to real experimental data from MCI/AD patients. RESULTS: Deep-SHAP significantly predicted cognition using simulated regional features and identified the ground-truth simulated regions as the most significant multivariate predictors. When applied to experimental MRI data, Deep-SHAP revealed that the insula, lateral occipital, medial frontal, temporal pole, and occipital fusiform gyrus are the primary contributors to global cognitive decline in MCI/AD. Furthermore, when applied to experimental amyloid Pittsburgh compound B (PiB)-PET data, Deep-SHAP identified the key brain regions for global cognitive decline in MCI/AD as the inferior temporal, parahippocampal, inferior frontal, supratemporal, and lateral frontal gray matter. CONCLUSION: Deep-SHAP method uncovered the multivariate relationships between regional brain features and cognition, offering insights into the most critical modality-specific brain regions involved in MCI/AD mechanisms.