A Harmonized Visual Reading Framework for Tau PET Staging in Alzheimer Disease

Importance Tau positron emission tomography (PET) can detect and stage Alzheimer disease pathology; however, current binary regulatory-approved visual interpretation focuses on advanced disease, limiting early detection and patient stratification. Objective To develop and validate a harmonized tau PET visual reading framework across radiotracers that stages tau burden into 5 classes: negative, low, moderate, high, and atypical. Design, Setting, and Participants This prospective multicenter cross-sectional study among a cohort with head-to-head tau PET acquisitions was conducted from March 2022 to August 2025 and data analyzed from February to June 2026, with blinded visual reads performed by clinicians. The study was conducted at 9 sites across North America and Europe. Of those individuals enrolled in the HEAD (Head-to-Head Harmonization of Tau Tracers in Alzheimer's Disease) study, a proportion of participants aged 50 to 90 years who completed multitracer tau PET (2-4 scans) and cognitive assessments were included, spanning cognitively unimpaired to dementia. Exposures Tau PET with 18 F-MK-6240 (TAUKLARIFY, n = 681), 18 F-flortaucipir (Tauvid, n = 644), 18 F-RO948 (n = 150), and 18 F-PI-2620 (n = 149); all participants underwent amyloid-β (Aβ) PET and magnetic resonance imaging. Main Outcomes and Measures The primary outcomes were interrater and intertracer agreement for 5-class tau classification; prevalence ratio (PR) vs the regulatory-approved 18 F-flortaucipir framework; and associations with cognition, Aβ burden, and plasma phosphorylated tau 217 (p-tau217). Results Of 822 individuals enrolled in the HEAD study, 681 participants spanning cognitively unimpaired to dementia were included. Mean (SD) age was 69.3 (8.4) years, and 367 participants (53.9%) were female. The harmonized 5-class framework achieved excellent interrater agreement (κ = 0.77-0.85) and good to excellent intertracer agreement, highest between 18 F-MK-6240 and 18 F-flortaucipir (κ = 0.88). Compared with the regulatory-approved framework, the harmonized classification identified more tau-positive cognitively unimpaired participants (regulatory-approved binary: 26 of 364 participants; harmonized 18 F-flortaucipir: 49 of 364 [PR = 1.89; 95% CI, 1.31-2.70; P = .001]; harmonized 18 F-MK-6240: 71 of 364 [PR = 2.73; 95% CI, 1.95-3.83; P < .001]) and those with mild cognitive impairment (regulatory-approved binary: 100 of 223; harmonized 18 F-flortaucipir: 123 of 223 [PR = 1.23; 95% CI, 1.12-1.35; P < .001]; harmonized 18 F-MK-6240: 142 of 223 [PR = 1.42; 95% CI, 1.27-1.59; P < .001]), with convergence in dementia. Tau burden classes showed stepwise worsening of cognition, Aβ PET burden, and plasma p-tau217, with 1.4-fold, 3.2-fold, and 2.5-fold differences between the low and high tau classes, respectively. Conclusions and Relevance In this prospective multitracer cross-sectional study, a 5-class harmonized tau PET visual reading framework showed high interrater and intertracer agreement and detected more early-stage tau pathology than the regulatory-approved binary approach, with tau burden classes tracking stepwise with cognition and biomarkers. These findings support a standardized, tracer-agnostic framework for diagnostic categorization, therapeutic window identification, and clinical trial stratification.