Personalised regional modelling predicts tau progression in the human brain

Aggregation of the hyperphosphorylated tau protein is a central driver of Alzheimer’s disease, and its accumulation exhibits a rich spatiotemporal pattern that unfolds during the course of the disease, sequentially progressing through the brain across axonal connections. It is unclear how this spatiotemporal process is orchestrated, namely, to what extent the spread of pathologic tau is governed by transport between brain regions, local production, or both. To address this, we develop a mechanistic model from tau PET data to describe tau dynamics along the Alzheimer’s disease timeline. Our analysis reveals longitudinal changes in production and transport dynamics in two independent cohorts, with subjects in the early stage of the disease exhibiting transport-dominated spread, consistent with an initial spread of pathological tau seeds, and subjects in the late stage disease characterized primarily by local tau production. Further, we demonstrate that the model can predict accurately subject-specific longitudinal tau accumulation at the regional level, potentially providing a new clinical tool to monitor and classify patient disease progression.Author summary: A mathematical model explains difference between early and late tau protein dynamics in Alzheimer’s, showing stage-specific shifts from transport to local production. The accumulation of aggregated tau shows a complex spatio-temporal pattern during the course of the Alzheimer’s Disease, but how these changes are orchestrated is unclear. This modeling study describes tau protein dynamics in Alzheimer’s disease, showing stage-specific shifts in its local production and transport.