In this cohort study of 490 individuals without dementia, plasma P-tau217 levels were elevated in amyloid-β–positive cognitively unimpaired participants before insoluble tau aggregates became detectable by tau-PET; modeling approaches predicted that both plasma and cerebrospinal fluid P-tau217 increased before tau-PET in the entorhinal cortex followed by more widespread cortical tau-PET changes. This evidence concerns the gene MAPT and dementia.