A Multilayer Network Analysis of Alzheimer's Disease Pathogenesis: Roles for P-tau, Synaptic Peptides, and Physical Activity

Introduction: In the aging brain, cognitive abilities emerge from the coordination of complex pathways arising from a balance between protective lifestyle and environmental factors and accumulation of neuropathologies.

Methods: As part of the Rush Memory and Aging Project (n = 440), we measured accelerometer-based actigraphy, cognitive performance, and after brain autopsy, selected reaction monitoring mass spectrometry. Multilevel network analysis was used to examine the relationships among the molecular machinery of vesicular neurotransmission, Alzheimer's disease (AD) neuropathology, cognition, and late-life physical activity.

Results: Synaptic peptides involved in neuronal secretory function were the most influential contributors to the multilayer network, reflecting the complex interdependencies among AD pathology, synaptic processes, and late-life cognition. Older adults with lower physical activity evidenced stronger adverse relationships among phosphorylated tau peptides, markers of synaptic integrity, and tangle pathology.

Discussion: Network-based approaches simultaneously model interdependent biological processes and advance understanding of the role of physical activity in age-associated cognitive impairment.

Highlights: Network-based approaches simultaneously model interdependent biological processes. Secretory synaptic peptides were influential contributors to the multilayer network. Older adults with lower physical activity had adverse relationships among pathology. There was interdependence among phosphorylated tau, synaptic integrity, and tangles. Network methods elucidate the role of physical activity in cognitive impairment.