Pathological tau spreads through communicating brain regions in human Alzheimer's disease

Vogel, J.; Iturria-Medina, Y.; Strandberg, O. T.; Smith, R.; Evans, A. C.; Hansson, O.; for the Alzheimer's Disease Neuroimaging Initiative,; the Swedish BioFINDER Study,

doi:10.1101/555821

bioRxiv · 10.1101/555821

Pathological tau spreads through communicating brain regions in human Alzheimer's disease

Vogel, J.·Iturria-Medina, Y.·Strandberg, O. T.·Smith, R.·Evans, A. C.·Hansson, O.·for the Alzheimer's Disease Neuroimaging Initiative,·the Swedish BioFINDER Study,

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Abstract

Tau is one of the two pathological hallmarks of Alzheimers disease, and bears a much closer relationship to local neurodegeneration and cognitive impairment than the other hallmark, {beta}-amyloid. Cell and rodent models have shown evidence that tau spreads from cell to cell through anatomical neuronal connections, and that this process is facilitated by the presence of {beta}-amyloid. We test this hypothesis in humans by using an epidemic spreading model (ESM) to simulate the spread of tau over human neuronal connections, and we compare the simulated pattern of progression to the observed pattern measured in the brains of 312 individuals on the Alzheimers disease spectrum, using PET. Fitting our model, we found that the majority of variance in the overall pattern of tau progression could be explained by diffusion of an agent through the human connectome, measured using either functional connectivity or diffusion tractography. These models far exceeded chance, and outperformed models testing the extracellular spread of tau over Euclidian space. Surprisingly, the ESM predicted the spatial patterns of tau irrespective of whether subjects demonstrated evidence for brain {beta}-amyloid. In addition, in {beta}-amyloid-positive subjects only, regions with greater amyloid burden showed greater tau than predicted by connectivity patterns, suggesting a role of amyloid in accelerating the spread of tau in certain isocortical regions. Altogether, our results provide strong evidence that tau spreads through neuronal communication pathways even in normal aging, and that this process is accelerated by the presence of brain {beta}-amyloid.

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Vogel, J., Iturria-Medina, Y., Strandberg, O. T., Smith, R., Evans, A. C., Hansson, O., for the Alzheimer's Disease Neuroimaging Initiative,, the Swedish BioFINDER Study,. 2019-02-20. Pathological tau spreads through communicating brain regions in human Alzheimer's disease. https://doi.org/10.1101/555821

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