Time between milestone events in the Alzheimer's disease amyloid cascade

ObjectiveEstimate the time-course of the spread of key pathological markers and the onset of cognitive dysfunction in Alzheimers disease. MethodsIn a cohort of 336 older adults, ranging in cognitive functioning, we estimated the time of initial changes of A{beta}, tau, and decreases in cognition with respect to the time of A{beta}-positivity. ResultsSmall effect sizes of change in CSF A{beta}42 and regional A{beta} PET were estimated to occur several decades before A{beta}-positivity. Increases in CSF tau occurred 11-12 years before A{beta}-positivity. Temporoparietal tau PET showed increases 4-5 years before A{beta}-positivity. Subtle cognitive dysfunction was observed 7-9 years before A{beta}-positivity. ConclusionsIncreases in tau and cognitive dysfunction occur years before the presence of significant A{beta}. Explicit estimates of the time for these events provide a clearer picture of the time course of the amyloid cascade and identify potential windows for specific treatments.