Guilherme Povala, Bruna Bellaver, Firoza Z Lussier, Lívia Amaral, Guilherme Bauer‐Negrini, Pamela C L Ferreira, Andreia Rocha, Emma Ruppert, Marina Scop Medeiros, Cécile Tissot, William J Jagust, Joseph C. Masdeu, Juan Fortea, Dana L. Tudorascu, David N. Soleimani-Meigooni, Val Lowe, Hwamee Oh, Belen Pascual, Brian A. Gordon, Pedro Rosa-Neto, Suzanne L. Baker, Tharick A. Pascoal, Tharick A Pascoal, Cristiano S. Aguzzoli, Lívia Amaral, Selma Avdagic, Suzanne L. Baker, Guilherme Bauer-Negrini, Bruna Bellaver, Tevy Chan, Ann D. Cohen, Emerine Cummings, Álvaro de Oliveira Franco, Vladimir Fonov, Tatiana Foroud, Juan Fortea, Brian A. Gordon, Danielle Gray, Xiaoyang Hu, Yasser Iturria-Medina, Wan Lu Jia, Jesse Klostranec, Douglas T. Leffa, Val Lowe, Pâmela Lukasewicz Ferreira, Firoza Z. Lussier, Joseph C. Masdeu, Marina S. Medeiros, Maxime Montembault, Rayan Mroué, Hwamee Oh, Markley S. Oliveira, Belen Pascual, Tharick A. Pascoal, Belen Pascual, Guilherme Povala, Karine Provost, Nesrine Rahmouni, Andreia Rocha, Matheus S. Rodrigues, Pedro Rosa-Neto, Emma Ruppert, Pampa Saha, Juli Singer, Carolina Soares, David N. Soleimani-Meigooni, Jenna Stevenson, Victoria Tate, Cécile Tissot, Arthur W. Toga, Hsin-Yeh Tsai, Dana L. Tudorascu, Raphael L. Tuma, Paolo Vitali
Background Tau PET imaging has emerged as a critical biomarker for Alzheimer's disease, informing diagnosis, staging, and therapeutic selection. We investigated whether PET tracer selection alters tau detection. Methods We conducted a prospective, multicentre, non-randomised, within-participant comparison of [ 18 F]flortaucipir (Tauvid), currently used in clinical settings in the USA and Europe, and [ 18 F]MK6240, an investigational tau PET tracer. Participants were recruited from eight north American sites and underwent tau PET, amyloid-β (Aβ) PET, and detailed cognitive assessments. Tau PET with both agents was acquired within a 45-day window. Coprimary outcomes were the discriminative accuracy for Alzheimer's disease-related cognitive impairment and the frequency of tau positivity in early medial temporal lobe (MTL) and late neocortical regions. The study is registered with ClinicalTrials.gov, NCT05361382. Findings Between March 2, 2022, and Aug 27, 2025, 775 individuals were enrolled, with 682 completing all procedures (373 [55%] female, 309 [45%] male; 38 [6%] aged 19–27 years, 214 [31%] aged 50–65 years, and 430 [63%] aged 65–89 years). 32 (5%) participants identified as Hispanic or Latino. 637 (93%) identified as White, 24 (4%) as Black or African American, 16 (2%) as Asian, and five (1%) as other. In addition, 49 (7%) individuals were identified as being from a rural area. [ 18 F]MK6240 showed greater accuracy than [ 18 F]flortaucipir in distinguishing Alzheimer's disease from non-Alzheimer's disease impairment (area under the curve 0·93, 95% CI 0·89–0·95 vs 0·86, 0·75–0·91; p<0·0001). Among the older adults, tau positivity status was concordant in 560 (87%) for MTL and 603 (94%) for neocortical regions. In cognitively unimpaired participants, [ 18 F]MK6240 identified twice as many MTL-positive cases as [ 18 F]flortaucipir (n=54 [15%] vs n=23 [6%]). Prevalence ratio in Aβ-positive was 2·43 (95% CI 1·50–3·94; p=0·0003), identifying 23 additional cases per 100. Among discordant cases, 75 (89%) were [ 18 F]MK6240-positive only and had higher Aβ burden (p<0·0001), APOEε4 frequency (p<0·0001), and cognitive impairment (p=0·0043) than those negative on both tracers. Neocortical tau positivity was more frequent with [ 18 F]MK6240 than with [ 18 F]flortaucipir in cognitively impaired individuals (80 [28%] vs 46 [16%]). Prevalence ratio in Aβ-positive was 1·74 (95% CI 1·32–2·29; p<0·0001), identifying 15 additional mild cognitive impairment and 21 dementia cases per 100. Interpretation Tau PET tracer selection influences the frequency of detection of tau pathology across the ageing and Alzheimer's disease spectrum. Compared with [ 18 F]flortaucipir, [ 18 F]MK6240 identified more individuals with tau pathology in cognitively unimpaired and cognitively impaired individuals, with direct implications for patient stratification in clinical trials and more precise guidance for therapeutic decision-making. Funding National Institute on Aging.