Spread of pathological tau proteins through communicating neurons in human Alzheimer\u2019s disease

Jacob W Vogel,Yasser Iturria-Medina,Ruben Smith,Alan C Evans,Olof T Strandberg,Elizabeth Levitis,Alzheimer’s Disease Neuroimaging Initiative ,Swedish Biofinder Study ,Oskar Hansson

doi:10.1038/s41467-020-15701-2

Jacob W Vogel, Yasser Iturria-Medina + Show 7 more

Open Access

https://doi.org/10.1038/s41467-020-15701-2

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Abstract

Tau is a hallmark pathology of Alzheimer’s disease, and animal models have suggested that tau spreads from cell to cell through neuronal connections, facilitated by β-amyloid (Aβ). We test this hypothesis in humans using an epidemic spreading model (ESM) to simulate tau spread, and compare these simulations to observed patterns measured using tau-PET in 312 individuals along Alzheimer’s disease continuum. Up to 70% of the variance in the overall spatial pattern of tau can be explained by our model. Surprisingly, the ESM predicts the spatial patterns of tau irrespective of whether brain Aβ is present, but regions with greater Aβ burden show greater tau than predicted by connectivity patterns, suggesting a role of Aβ in accelerating tau spread. Altogether, our results provide evidence in humans that tau spreads through neuronal communication pathways even in normal aging, and that this process is accelerated by the presence of brain Aβ.

Highlights

Tau is a hallmark pathology of Alzheimer’s disease, and animal models have suggested that tau spreads from cell to cell through neuronal connections, facilitated by β-amyloid (Aβ)
Tau tangle aggregation in the medial temporal lobes is a common feature of normative aging[9,10,11], itself associated with subtle cognitive effects[12,13]
Post-mortem studies cannot provide direct evidence of cell-to-cell spread, and while animal models have proven tau can spread through neuronal connections under certain unnatural conditions, they cannot prove that this phenomenon occurs naturally in humans

Summary

Introduction

Tau is a hallmark pathology of Alzheimer’s disease, and animal models have suggested that tau spreads from cell to cell through neuronal connections, facilitated by β-amyloid (Aβ). Neurofibrillary tangles first appear in the transentorhinal cortex, before spreading to the anterior hippocampus, followed by adjacent limbic and temporal cortex, association isocortex, and to primary sensory cortex[10,17,18,19] This very particular pattern has led many to speculate that pathological tau itself, or a pathological process that incurs tau hyper-phosphorylation and toxicity, may spread directly from cell to cell through anatomical connections[20,21]. We test the tau-spreading hypothesis by placing a “tau seed” in the entorhinal cortex, simulating its diffusion through measured functional and anatomical connections, and comparing the simulated pattern of global tau spread with the actual pattern derived from tau-PET scans of 312 individuals This method allows for a cascade of secondary tau seeding events to occur along a network over time, more closely simulating proposed models of tau spread in the brain. We examine how the behavior of our model interacts with brain β-amyloid and what it can tell us about asymmetric tau distribution

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