UCSF

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 well-known 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. Impact statement Graph theory is a powerful new approach that is transforming the study of brain processes. There do not exist many focused reviews of the subfield of graph modeling of how Alzheimer's and other dementias propagate within the brain network, and how these processes can be mapped mathematically. By providing timely and topical review of this subfield, we fill a critical gap in the community and present a unified view that can serve as an in silico test-bed for future hypothesis generation and testing. We also point to several open and unaddressed questions and controversies that future practitioners can tackle.