The role of directionality in determining spatiotemporal tau pathology differs between AD-Like and Non-AD-Like mouse models

IntroductionCurrent research indicates divergent spatiotemporal tauopathy progression between conditions and implicates transsynaptic connectome-based spread as a main mechanism. We examine tauopathy and connectome interactions to investigate why different spatiotemporal patterns of pathology arise. MethodsWe test whether divergent spatiotemporal tau pathology patterns from 15 mouse-model datasets can be explained by a directional bias in tau transmission along fiber tracts via a mathematical model called Directed Network Transmission (DNT). ResultsAmyloid-comorbid tauopathic mouse models meant to mimic AD demonstrate spatiotemporal tauopathy patterns consistent with retrograde direction spread biases. Non-amyloid-comorbid mice demonstrate no consistent spread biases. Further, canonically early tau pathology regions in AD are implicated as having earliest pathology in a simulation with random tauopathy seeding locations with retrograde biased spread. DiscussionThese results implicate directional biases in tau pathology spread along fiber tracts as a strong candidate explanation for divergent spatiotemporal tau progression between conditions.