Abstract
INTRODUCTION: Alzheimer's Disease (AD) is a complex neurodegenerative disorder with numerous known risk factors. Identification of which genetic factors are causal drivers is difficult due to the long disease prodrome in an inaccessible organ. The application of integrative, systems-level approaches are crucial for addressing this complexity. METHODS: Sixteen biological domain specific interaction networks were derived from the top AD risk-enriched proteins within each domain. Weighted key driver analysis identified influential hub nodes within each network. RESULTS: Distinct processes and drivers were identified within each domain's network. Domains including Structural Stabilization, Endolysosome, and Lipid Metabolism were especially influential. Integrating key drivers across domains identified consistent drivers such as CTNNB1, ACSL1, and ALDH3A2, suggesting fundamental roles contributing to AD risk. DISCUSSION: This highly integrative network-based approach identified context-dependent drivers and enabled the inference of interactions between domains. The identified drivers suggest potential targets for future therapeutic development.