Integrating Infection Burden and Multimodal Biomarkers for Early Detection of Alzheimers Disease: A Sheaf-ML Framework.

Alzheimers disease (AD) remains a major global health challenge, with growing evidence linking chronic infections, immune aging, and neurodegeneration. Grounded in the Antimicrobial Protection Hypothesis, this study introduces a sheaf-theoretic machine learning framework, Sheaf-ML, for integrating multimodal health data and assessing infection-related cognitive risk. Sheaf-ML constructs a unified patient-level representation that coherently combines diverse data streamsincluding serological infection markers, cognitive assessments, cardiovascular and metabolic measures, nutritional and behavioral evaluationswhile preserving the intrinsic structure and relationships of each modality. Applying this framework to the Harmonized LASI-DAD dataset (N = 6168), we modeled six clinically motivated domains (Infection, Cognition, Mental Health, Cardiovascular, Nutrition, and Demographics) and integrated them into a topologically consistent representation using learnable cross-domain mappings and consistency constraints. The sheaf-integrated embeddings revealed clinically meaningful interactions: infection burden was linked with cardio-vascular, nutritional, and cognitive outcomes, highlighting system-level coordination across modalities. Using these embeddings, Sheaf-ML produced interpretable patient-level predictions and identified the most influential features both globally and individually. We further derived an Infection Burden Index (IBI), which quantified patient-level infection-related risk. Patients exceeding the 80th percentile were flagged as early-warning cases, corresponding to approximately 20% of the cohort, demonstrating actionable stratification for clinical monitoring. This study provides the first empirical evidence that sheaf-based architectures can integrate multimodal health data in a clinically interpretable manner, uncover biologically meaningful interactions, and support patient-specific risk prediction. By linking population-level patterns with individualized insights, Sheaf-ML establishes a foundation for scalable, interpretable, and equitable precision models of infection-related cognitive decline in Alzheimers disease.