Systems biology of Alzheimer’s Disease: a scoping review of key pathways and mechanisms

Alzheimer’s Disease (AD) is a progressive and ultimately fatal neurodegenerative disorder, representing the most common form of dementia and affecting nearly 7 million people in the United States. For over a century, research has centered on hallmark AD pathologies—extracellular β-amyloid (Aβ) plaques and intracellular neurofibrillary tangles composed of hyperphosphorylated tau (pTau). While these mechanisms remain central to our understanding of the Disease, the underlying molecular events and broader biological pathways driving AD are still not fully understood. Precision medicine for AD and related dementias (ADRD) requires a comprehensive understanding of neurodegenerative Disease through pathophysiologic biomarkers for early detection, prediction of progression, and for evaluating response to treatment. Systems biology provides a powerful framework for this effort, leveraging multi-omics for biomarker discovery and elucidation of critical Disease pathways. The purpose of this scoping review is to identify and inform the field on key pathways being intensively investigated in AD/ADRD, including hallmark pathology, proteostasis, inflammation, oxidative stress, glucose metabolism, lipid dysregulation, neurotransmitter systems, synaptic integrity, neurogenesis, co-pathology- and sex-related pathways. Finally emerging biomarkers, tools and strategies for discovery and analysis are discussed, emphasizing advances related to the emerging precision medicine for AD.