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Abstract Background Functional connectivity (FC) biomarkers play a crucial role in the early diagnosis and mechanistic study of Alzheimer’s disease (AD). However, the identification of effective FC biomarkers remains challenging. In this study, we introduce a novel approach, the spatiotemporal graph convolutional network (ST-GCN) combined with the gradient-based class activation mapping (Grad-CAM) model (STGC-GCAM), to effectively identify FC biomarkers for AD. Methods This multi-center cross-racial retrospective study involved 2,272 participants, including 1,105 cognitively normal (CN) subjects, 790 mild cognitive impairment (MCI) individuals, and 377 AD patients. All participants underwent functional magnetic resonance imaging (fMRI) and T1-weighted MRI scans. In this study, firstly, we optimized the STGC-GCAM model to enhance classification accuracy. Secondly, we identified novel AD-associated biomarkers using the optimized model. Thirdly, we validated the imaging biomarkers using Kaplan–Meier analysis. Lastly, we performed correlation analysis and causal mediation analysis to confirm the physiological significance of the identified biomarkers. Results The STGC-GCAM model demonstrated great classification performance (The average area under the curve (AUC) values for different categories were: CN vs MCI = 0.98, CN vs AD = 0.95, MCI vs AD = 0.96, stable MCI vs progressive MCI = 0.79). Notably, the model identified specific brain regions, including the sensorimotor network (SMN), visual network (VN), and default mode network (DMN), as key differentiators between patients and CN individuals. These brain regions exhibited significant associations with the severity of cognitive impairment (p |
