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Neurodegenerative diseases involve progressive neuronal dysfunction, requiring the identification of specific pathological features for accurate diagnosis. While cerebrospinal fluid analysis and neuroimaging are commonly used, their invasive nature and high costs limit clinical applicability. Recently advances in plasma proteomics offer a less invasive and cost-effective alternative, further enhanced by machine learning (ML). However, most ML-based studies overlook synergetic effects from protein–protein interactions (PPIs), which play a key role in disease mechanisms. Although graph convolutional network and its extensions can utilize PPIs, they rely on locality-based feature aggregation, overlooking essential components and emphasizing noisy interactions. Moreover, expanding those methods to cover broader PPIs results in complex model architectures that reduce explainability, which is crucial in medical ML models for clinical decision-making. To address these challenges, we propose Protein–Protein Interaction-based eXplainable Graph Propagational Network (PPIxGPN), a novel ML model designed for plasma proteomic profiling of neurodegenerative biomarkers. PPIxGPN captures synergetic effects between proteins by integrating PPIs with independent effects of proteins, leveraging globality-based feature aggregation to represent comprehensive PPI properties. This process is implemented using a single graph propagational layer, enabling PPIxGPN to be configured by shallow architecture, thereby PPIxGPN ensures high model explainability, enhancing clinical applicability by providing interpretable outputs. Experimental validation on the UK Biobank dataset demonstrated the superior performance of PPIxGPN in neurodegenerative risk prediction, outperforming comparison methods. Furthermore, the explainability of PPIxGPN facilitated detailed analyses of the discriminative significance of synergistic effects, the predictive importance of proteins, and the longitudinal changes in biomarker profiles, highlighting its clinical relevance.

PPIxGPN: plasma proteomic profiling of neurodegenerative biomarkers with protein–protein interaction-based eXplainable graph propagational network