Longitudinal 18F-MK-6240 tau tangles accumulation follows Braak stages

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.