Alzheimer’s Disease as a Multi-Layer Network Disorder: A Systems Biology Framework Integrating Multi-Omics Mechanisms

Despite substantial progress in biomarker discovery and multi-omics profiling, several features of Alzheimer’s disease (AD), including prolonged compensated states, heterogeneous clinical trajectories, and marked stage-dependent therapeutic responses, remain difficult to integrate into a single mechanistic framework. In this review, we propose an integrative and testable conceptual framework that reframes AD as a single, progressive multi-layer network disorder whose dynamics arise from hierarchical constraint propagation and progressive loss of cross-scale coordination. Integrating evidence from human genetics, epigenomics, transcriptomics, proteomics, metabolomics, spatial biology, connectomics, and longitudinal biomarker studies, we examine how molecular, cellular, and circuit-level processes interact over time to shape disease progression. Within this framework, different omics measurements are interpreted as complementary representations of disease-related changes, rather than as independent molecular signatures. Disease progression reflects the gradual convergence of immune, metabolic, proteostatic, cytoskeletal, and synaptic stress, with overt cognitive impairment emerging when compensatory capacity is exceeded, producing threshold-like network destabilization. By explicitly linking biological scale, temporal hierarchy, and network structure, this synthesis extends prior network-medicine, connectomic, and multi-omics approaches into a testable framework for state-aware stratification, integrative analysis, and stage-appropriate therapeutic investigation in AD.