Increasing evidence indicates that Alzheimer’s disease (AD) develops from an intricate web of biochemical and cellular processes that extend far beyond amyloid and tau accumulation. This growing recognition surrounding the diversity of AD pathophysiology underscores the need for holistic systems-based approaches to explore AD pathogenesis. Using isobaric tandem mass tag (TMT) based mass spectrometry methods we describe how network-based proteomics has provided an informative framework for the complex protein pathophysiology underlying AD. Furthermore, we outline how the global brain network proteome can be leveraged to advance translational efforts including the discovery and validation of novel protein biomarkers in cerebrospinal fluid.