Cohort-specific Boolean models highlight different regulatory modules during Parkinson's disease progression

Parkinson's Disease (PD) is a multifaceted neurodegenerative disorder characterised by complex molecular dysregulations and diverse comorbidities. It is critical to decode the molecular pathophysiology of PD, which involves complex molecular interactions and their changes over time. Systems medicine approaches can help with this by a) encoding knowledge about the mechanisms into computational models and b) simulating these models using patient-specific omics data. This study employs the PD map, a detailed repository of PD-related molecular interactions, as a comprehensive knowledge resource. We aim to dissect and understand the intricate molecular pathways implicated in PD by using logical modelling. This approach is essential for capturing the dynamic interplay of molecular components that contribute to the disease. We incorporate cohort-level and real-world patient data to ensure our models accurately reflect PD's subtype-specific pathway deregulations. This integration is crucial for addressing the heterogeneity observed in PD manifestations and responses to treatment. To combine logical modelling with empirical data, we rely on Probabilistic Boolean Networks (PBNs).These networks provide a robust framework, capturing the stochastic nature of molecular interactions and offering insights into the variable progression of the disease. By combining logical modelling with empirical data through PBNs, we achieve a more refined and realistic representation of PD's molecular landscape. The findings provide insights into the molecular mechanisms of PD. We identify key regulatory biomolecules and pathways that differ significantly across PD subtypes. These discoveries have substantial implications for the development of precise medical treatments. The study provides hypothesis for targeted therapeutic interventions by linking molecular dysregulation patterns to clinical phenotypes and advancing our understanding of PD progression and patient stratification. ### Competing Interest Statement The authors have declared no competing interest.