Model ablation performance evaluation table.

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder with limited diagnostic tools and poorly understood molecular underpinnings. Although multi-omics technologies hold promise for early detection, integrating unpaired transcriptomic and epigenetic data remains a major challenge due to modality heterogeneity and small sample sizes. We present AE-Trans, an interpretable dual-channel Transformer framework that aligns RNA and DNA methylation data through cross-modal reconstruction and multi-head attention. AE-Trans achieves superior performance on prefrontal cortex datasets (accuracy = 0.9736, AUC = 0.9910) and demonstrates strong generalizability to external regions temporal cortex cohorts across brain regions (accuracy = 0.7389, AUC = 0.8432). To validate the performance within the same brain region, we tested AE-Trans on an external unpaired multi-omics dataset from the prefrontal cortex. Additionally, we validated the model on a paired multi-omics dataset to assess whether it could achieve good results in real-world scenarios. In the unpaired dataset from the external same brain region, AE-Trans achieved an accuracy of (accuracy = 0.87) and AUC of (AUC = 0.94), while in the real-world paired multi-omics dataset, the accuracy was (accuracy = 0.88) and AUC was (AUC = 0.93). These results demonstrate that AE-Trans not only validates well on external unpaired datasets, but also generalizes effectively to real-world multi-omics paired datasets, highlighting its robustness in practical applications. Through counterfactual integrated gradients, we identified key features associated with immune regulation, hormonal signaling, and neuronal metabolism. These were validated via pathway enrichment and logistic regression (AUC = 0.9749), confirming the biological relevance of model-derived markers. Furthermore, AE-Trans generalized well to two independent RNA datasets, where latent representations not only improved classification (AUCs = 0.92 and 0.89) but also stratified patients into subgroups with significantly different prognoses. These results highlight AE-Trans as a robust and explainable tool for multi-omics integration, supporting early diagnosis, biomarker discovery, and individualized risk prediction in Alzheimer’s disease.