Amplification, not spreading limits rate of tau aggregate accumulation in Alzheimer's disease
2020
Both the replication of protein aggregates and their spreading throughout the brain are
implicated in the progression of Alzheimer9s 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 are able to quantify their
replication rate in human brains. Remarkably, we obtain comparable rates in several
different datasets, with 5 different methods of tau quantification, from seed
amplification assays in vitro to tau PET studies in living patients. Our results suggest
that the overall rate of accumulation of tau in neocortical regions is limited not by
spreading between brain regions but by local replication, which doubles the number of
seeds every ~5 years. Thus, we propose that limiting local replication constitutes the
most promising strategy to control tau accumulation during AD.
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