Understanding the complex interplay between tau, amyloid and the network in the spatiotemporal progression of Alzheimer’s Disease

It is well known that Aβ 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 enzymtic cross-species coupling of amyloid and tau. We first established that the spatiotemporal evolution of theoretical tau and Aβ correctly predicts empirical patterns of regional Aβ, tau and atrophy. Remarkably, the introduction of a 1-way Aβ→tau interaction was critical to the models’ 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.