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

Tau positron emission tomography (PET) staging is increasingly used to stratify Alzheimers 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 [18F]Flortaucipir and [18F]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 [18F]MK6240 assigned a higher stage, on average approximately one stage above [18F]Flortaucipir. [18F]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 [18F]MK6240 and ~3 for [18F]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 [18F]MK6240 systematically assigning higher stages than [18F]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.

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Publication Details

Journal
medRxiv
Published
2026-11-02
DOI
https://doi.org/10.64898/2026.11.01.26367034
Primary Topic
Dementia and Cognitive Impairment Research
Type
preprint
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preprint

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

Val J. Lowe, Dana Tudorascu, Tharick Ali Pascoal, João Pedro Ferrari‐Souza et al.
medRxiv
Dementia and Cognitive Impairment Research
preprint

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

Val J. Lowe, Dana Tudorascu, Tharick Ali Pascoal, João Pedro Ferrari‐Souza, Juan Fortea, Tobey J. Betthauser, Guilherme Povala, Belén Pascual, Joseph C. Masdeu, Carolina Soares, Guilherme Bauer‐Negrini, Álvaro de Oliveira Franco, Nesrine Rahmouni, Pâmela C.L. Ferreira, Emma Patrice Ruppert, Arthur C. Macedo, Thomas K. Karikari, Bruna Bellaver, David N. Soleimani‐Meigooni, Suzanne L. Baker, Firoza Zubeida Lussier, Lívia Amaral, Cécile Tissot, Andréia Silva da Rocha, Brian Andrew Gordon, Pedro Rosa‐Neto, Jeffrey L. Evelhoch, Hwamee Oh, Rayan Mroué, HEAD study, Marina Scoop Medeiros, Markley Oliveira-Junior, Matheus Rodrigues
preprint en

Abstract

Tau positron emission tomography (PET) staging is increasingly used to stratify Alzheimers 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 [18F]Flortaucipir and [18F]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 [18F]MK6240 assigned a higher stage, on average approximately one stage above [18F]Flortaucipir. [18F]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 [18F]MK6240 and ~3 for [18F]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 [18F]MK6240 systematically assigning higher stages than [18F]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.

medRxiv
Mayo Clinic (US), University of Wisconsin–Madison (US), Lawrence Berkeley National Laboratory (US), University of Pittsburgh (US), University of California, San Francisco (US), Washington University in St. Louis (US), Brown University (US), Hospital de Sant Pau (ES), Hospital Moinhos de Vento (BR), Houston Methodist Research Institute (US), McGill University (CA)
Dementia and Cognitive Impairment Research
DOIOpen Access PDFOpenAlex
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