Understanding the complex interplay between tau, amyloid and the network in the spatiotemporal progression of Alzheimer's Disease
It is well known that A{beta} and tau proteins are deposited stereotypically in brain regions to cause Alzheimer's disease. The interaction of amyloid and tau in neurodegenerative diseases is a central feature and key to understanding AD pathophysiology. However their mechanisms are controversial, and many aspects do not fit current theories that rely on cell-autonomous factors. While cell culture and animal studies point to various interaction mechanisms between amyloid and tau, their causal direction and mode (local, remote or network-mediated) remain unknown in human subjects. Further, cross-protein interaction is yet to be reconciled with canonical observations that the two species do not co-localize significantly either in space or in time, and do not target the same neuronal populations. To answer these questions quantitatively, in this study we employed a mathematical reaction-diffusion model encoding the biophysical mechanisms underlying self-assembly, trans-neuronal network propagation and cross-species coupling of amyloid and tau. We first established that the spatiotemporal evolution of theoretical tau and A{beta} correctly predicts empirical patterns of regional A{beta}, tau and atrophy. Remarkably, the introduction of a 1-way A{beta}-->tau interaction was critical to the model's success. In comparison, both the non-interacting and the 2-way interaction models were significantly worse. We also found that network-mediated spread is essential; alternative modes of spread involving proximity or fiber length fare much worse. This mathematical exposition of the "pas de deux" of co-evolving proteins provides crucial quantitative and whole-brain support to the concept of amyloid-facilitated-tauopathy rather than the classic amyloid-cascade or pure-tau hypotheses, and helps explain certain known but poorly understood aspects of AD.