Graph Models of Pathology Spread in Alzheimer's Disease: An Alternative to Conventional Graph Theoretic Analysis

Background: Graph theory and connectomics are new techniques for uncovering disease-induced changes in the brain's structural network. Most prior studied have focused on network statistics as biomarkers of disease. However, an emerging body of work involves exploring how the network serves as a conduit for the propagation of disease factors in the brain and has successfully mapped the functional and pathological consequences of disease propagation. In Alzheimer' s disease (AD), progressive deposition of misfolded proteins amyloid and tau is wellknown to follow fiber projections, under a "prion-like" trans-neuronal transmission mechanism, through which misfolded proteins cascade along neuronal pathways, giving rise to network spread. Methods: In this review, we survey the state of the art in mathematical modeling of connectome-mediated pathology spread in AD. Then we address several open questions that are amenable to mathematically precise parsimonious modeling of pathophysiological processes, extrapolated to the whole brain. We specifically identify current formal models of how misfolded proteins are produced, aggregate, and disseminate in brain circuits, and attempt to understand how this process leads to stereotyped progression in Alzheimer's and other related diseases. Conclusion: This review serves to unify current efforts in modeling of AD progression that together have the potential to explain observed phenomena and serve as a test-bed for future hypothesis generation and testing in silico.