In vivo rate-determining steps of tau seed accumulation in Alzheimer’s disease

Abstract

Both the replication of protein aggregates and their spreading throughout the brain are implicated in the progression of Alzheimer’s disease (AD). However, the rates of these processes are unknown and the identity of the rate-determining process in humans has therefore remained elusive. By bringing together chemical kinetics with measurements of tau seeds and aggregates across brain regions, we can quantify their replication rate in human brains. Notably, we obtain comparable rates in several different datasets, with five different methods of tau quantification, from postmortem seed amplification assays to tau PET studies in living individuals. Our results suggest that from Braak stage III onward, local replication, rather than spreading between brain regions, is the main process controlling the overall rate of accumulation of tau in neocortical regions. The number of seeds doubles only every ∼5 years. Thus, limiting local replication likely constitutes the most promising strategy to control tau accumulation during AD.