Tracking longitudinal tau tangles accumulation across the Alzheimer's disease continuum is crucial to better understand the natural history of tau pathology and for clinical trials. Although the available first-generation tau PET tracers detect tau accumulation in symptomatic individuals, their nanomolar affinity offers limited sensitivity to detect early tau accumulation in asymptomatic subjects. Here, we hypothesized the novel sub-nanomolar affinity tau tangles tracer [18F]MK-6240 can detect longitudinal tau accumulation in asymptomatic and symptomatic subjects. We studied 125 living individuals (65 cognitively unimpaired elderly amyloid-β negative, 22 cognitively unimpaired elderly amyloid-β positive, 21 mild cognitive impairment amyloid-β positive, 17 Alzheimer's disease dementia amyloid-β positive) with baseline amyloid-β [18F]AZD4694 PET and baseline and follow-up tau [18F]MK-6240 PET. [18F]MK-6240 standardized uptake value ratio (SUVR) was calculated at 90-110 min after tracer injection and used the cerebellar crus I as the reference region. In addition, we assessed in vivo [18F]MK-6240 SUVR and postmortem phosphorylated tau pathology in two Alzheimer's disease dementia participants who deceased after the PET scans. We found that cognitively unimpaired amyloid-β negative individuals had significant longitudinal tau accumulation confined to PET Braak-like stage I (3.9%) and II (2.8%) areas. Cognitively unimpaired amyloid-β positive showed greater tau accumulation in Braak-like stage I (8.9%), compared to later Braak stages. Mild cognitive impairment and Alzheimer's dementia amyloid-β positive patients showed tau accumulation in Braak III-VI, but not in Braak I-II regions. Cognitively impaired amyloid-β positive individuals that were Braak II-IV at baseline showed 4.6-7.5% annual increase in tau accumulation in Braak III-IV regions, whereas cognitively impaired amyloid-β positive Braak V-VI at baseline had 8.3-10.7% annual increase in Braak V-VI regions. Neuropathological assessments confirmed the PET-based Braak stages V-VI observed in the two brain donors. Our results suggest that [18F]MK-6240 SUVR is able to detect longitudinal tau accumulation in asymptomatic and symptomatic Alzheimer's disease. The highest magnitude of [18F]MK-6240 SUVR accumulation moved from medial temporal to sensorimotor cortex across the disease clinical spectrum. Trials using [18F]MK-6240 SUVR in cognitively unimpaired would be required to use regions-of-interest corresponding to early Braak stages, whereas trials in cognitively impaired would benefit from using regions-of-interest in late Braak stages. Anti-tau trials should take into consideration individuals' baseline PET Braak-like stage to minimize the variability introduced by the hierarchical accumulation of tau tangles in the human brain. Finally, our postmortem findings supported [18F]MK-6240 SUVR as a biomarker to stage tau pathology in Alzheimer's disease patients.