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

INTRODUCTIONThe interaction of amyloid and tau in neurodegenerative diseases is a central feature of AD pathophysiology. While experimental studies point to various interaction mechanisms, their causal direction and mode (local, remote or network-mediated) remain unknown in human subjects. The aim of this study was to compare mathematical reaction-diffusion models encoding distinct cross-species couplings to identify which interactions were key to model success. METHODSWe tested competing mathematical models of network spread, aggregation, and amyloid-tau interactions on publicly available data from ADNI. RESULTSAlthough network spread models captured the spatiotemporal evolution of tau and amyloid in human subjects, the model including a one-way amyloid-to-tau aggregation interaction performed best. DISCUSSIONThis mathematical exposition of the "pas de deux" of co-evolving proteins provides quantitative, 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.