Comparison of [18F]flortaucipir and [18F]MK6240 for the detection of tau pathology in Alzheimer's disease (HEAD): a multicentre, prospective, cross-sectional, within-participant study.

Abstract (English)

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 [¹⁸F]flortaucipir (Tauvid), currently used in clinical settings in the USA and Europe, and [¹⁸F]MK6240, an investigational tau PET tracer. Participants were recruited from eight north American sites and underwent tau PET, amyloid-&#x3b2; (A&#x3b2;) 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. [¹⁸F]MK6240 showed greater accuracy than [¹⁸F]flortaucipir in distinguishing Alzheimer's disease from non-Alzheimer's disease impairment (area under the curve 0&#xb7;93, 95% CI 0&#xb7;89-0&#xb7;95 vs 0&#xb7;86, 0&#xb7;75-0&#xb7;91; p<0&#xb7;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, [¹⁸F]MK6240 identified twice as many MTL-positive cases as [¹⁸F]flortaucipir (n=54 [15%] vs n=23 [6%]). Prevalence ratio in A&#x3b2;-positive was 2&#xb7;43 (95% CI 1&#xb7;50-3&#xb7;94; p=0&#xb7;0003), identifying 23 additional cases per 100. Among discordant cases, 75 (89%) were [¹⁸F]MK6240-positive only and had higher A&#x3b2; burden (p<0&#xb7;0001), APOE&#x3b5;4 frequency (p<0&#xb7;0001), and cognitive impairment (p=0&#xb7;0043) than those negative on both tracers. Neocortical tau positivity was more frequent with [¹⁸F]MK6240 than with [¹⁸F]flortaucipir in cognitively impaired individuals (80 [28%] vs 46 [16%]). Prevalence ratio in A&#x3b2;-positive was 1&#xb7;74 (95% CI 1&#xb7;32-2&#xb7;29; p<0&#xb7;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 [¹⁸F]flortaucipir, [¹⁸F]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.