Spread of pathological tau proteins through communicating neurons in human Alzheimer's disease

Jacob W. Vogel, Yasser Iturria-Medina, Olof T. Strandberg, Ruben Smith, Alan C. Evans, Oskar Hansson, for the Alzheimer’s Disease Neuroimaging Initiative, and the Swedish BioFinder Study

Jun 04, 2019

Received Date: 22nd May 19

Tau is one of the two pathological hallmarks of Alzheimer's 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 Alzheimer's 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.

Read in full at bioRxiv.

This is an abstract of a preprint hosted on an independent third party site. It has not been peer reviewed but is currently under consideration at Nature Communications.

Nature Communications

Nature Research, Springer Nature