A multilayer network analysis of Alzheimer's disease pathogenesis: Roles for p-tau, synaptic peptides, and physical activity

Abstract

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.

Keywords: Alzheimer's disease; aging; physical activity; post mortem brain; presynaptic proteins; proteomics; synaptopathy.

FIGURE 1

Multilayer network of synaptic peptides (white), synaptic protein–protein interactions (gray), pathological peptides (lime), and cellular pathology (teal). Hub nodes highlighted in pink. Edge weights represent the positive (blue) and negative (red) conditional dependencies between nodes. Fruchterman–Reingold layout whereby nodes closely positioned have stronger relationships.

FIGURE 2

Synaptic peptide network with six modules identified: module 1 (orange), module 2 (blue), module 3 (green), module 4 (yellow), module 5 (purple), and module 6 (red). Edge weights represent the positive (blue) and negative (red) conditional dependencies between nodes. Fruchterman–Reingold layout whereby nodes closely positioned have stronger relationships.

FIGURE 3

Stacked barplots of the proportion of synaptic peptides in each module by (left to right) cell type, subcellular localization, and primary function.

FIGURE 4

Boxplots of expected influence values of synaptic peptide nodes according to (A) the main function in the synaptic vesicle cycle and (B) the module membership.

FIGURE 5

A, Multilayer network of synaptic peptides (white), synaptic protein–protein interactions (gray), pathological peptides (lime), and cellular pathology (teal) for the higher physical activity group versus lower physical activity group. Hub nodes highlighted in pink. Nodes with an edge unique to the lower physical activity identified by bootstrap permutation testing are highlighted in cyan. Edge weights represent the positive (blue) and negative (red) conditional dependencies between nodes. Fruchterman–Reingold layout whereby nodes closely positioned have stronger relationships. B, Centrality measures (z scores) for all synaptic peptides (black), synaptic protein–protein interactions (gray), pathological peptides (lime), and cellular pathology (teal) nodes of the multilayer network. C, Schematic figure demonstrating the unbalanced triangle including two hub nodes in the multilayer network. Values are edge weights, with blue representing positive edges and red representing negative edges. High‐PA, higher physical activity group; Low‐PA, lower physical activity group.

FIGURE 6

Schematic depiction of multilayer network among older adults with lower physical activity, demonstrating the cellular pathology (teal), pathological peptide (lime), and synaptic peptide (white) layers, as well as the module 1 peptides (orange), module 2 peptides (blue), and hub nodes (highlighted in pink). Putative pathways for neurodegeneration are highlighted in red, and an edge unique to the lower physical activity group is highlighted in pink.