Tau PET Braak staging across the Alzheimer Disease continuum using Flortaucipir and MK6240

Tau positron emission tomography (PET) staging is increasingly used to stratify Alzheimer’s disease (AD), yet cross-tracer interchangeability remains unestablished. In a prospective head-to-head study of 682 individuals across the aging-to-AD continuum, we compared tau PET Braak staging derived from [ ¹⁸ F]Flortaucipir and [ ¹⁸ F]MK6240. While both tracers showed high internal adherence to hierarchical Braak patterns (89-92%), cross-tracer agreement was limited (43%, weighted κ = 0.54) and fell to 14- 23% at early-to-intermediate stages, a key window for therapeutic intervention. Discordance was strongly directional: in over 90% of discordant cases [ ¹⁸ F]MK6240 assigned a higher stage, on average approximately one stage above [ ¹⁸ F]Flortaucipir. [ ¹⁸ F]MK6240 upstaging was associated with greater Aβ burden, adverse plasma biomarker profiles, and worse cognitive performance. Stage-frequency benchmarking against an external neuropathological cohort (N = 4,422) revealed that PET staging lags neuropathology by ∼2 Braak stages for [ ¹⁸ F]MK6240 and ∼3 for [ ¹⁸ F]Flortaucipir in the early phases of disease, with progressive convergence at later stages. Tau PET Braak staging is internally coherent within tracers but not interchangeable across them, with [ ¹⁸ F]MK6240 systematically assigning higher stages than [ ¹⁸ F]Flortaucipir. This biologically meaningful discordance, most pronounced at early stages, has direct implications for patient selection and staging for clinical trials and practice, necessitating tracer- aware harmonization strategies.