Abstract
INTRODUCTION: Trans-synaptic connectome-based spread is a shared mechanism behind different tauopathic conditions, but they exhibit divergent spatiotemporal progression. One explanation is that conditions may incur directional biases in tau transmission along fiber tracts. METHODS: We examined this hypothesis using tau data from 11 distinct mouse models across four experimental studies. For this purpose, we extended a network-based spread model by incorporating net directionality along the connectome. RESULTS: Retrograde bias better predicted tau progression than anterograde bias, but our best-fitting biophysical models incorporate the mixed effects of both retrograde- and anterograde-directed spread, with notable tau-strain-specific differences. There was a nontrivial association between directionality bias and tau aggressiveness, with more virulent strains exhibiting less retrograde character. DISCUSSION: Our study implicates directional bias in tau transmission along fiber tracts as a general feature of tauopathy spread and a strong candidate for explaining for the diversity of spatiotemporal tau progression between conditions. HIGHLIGHTS: Connectome-based spread is a feature underpinning tauopathic diseases, including Alzheimer's Eleven mouse models of tauopathy across four studies were explored Mathematical models of retrograde and nondirectional spread performed better than anterograde Different mouse models of tauopathy exhibited distinct spread biases Retrograde-biased spread tended to be associated with less aggressive tau strains.