Detection of tau spatial extent using MK6240 and flortaucipir PET

INTRODUCTION: Tau PET enables in vivo quantification of neurofibrillary tangle spread, yet whether tau spatial extent (TSE) performs comparably across tracers remains unknown. METHODS: We performed a head-to-head comparison of Flortaucipir and MK6240 tau PET in 682 individuals across the AD continuum, quantifying TSE as the percentage of regional voxels exceeding a tracer-specific abnormality threshold and evaluated it as a metric of tracer comparability. RESULTS: MK6240 showed greater TSE than Flortaucipir (CU Aβ+, medial temporal lobe [MTL]: 42% vs 25%; dementia Aβ+, late neocortical: 55% vs 42%), reaching 50% detection probability at lower Aβ burden (Centiloid: MTL, 26 vs 45; late neocortical, 95 vs 118). TSE showed higher associations than SUVR with memory, Aβ PET, and plasma pTau217, particularly in the neo-late composite. Participants with intermediate tau involvement (TSE 25–50%), most below the SUVR positivity thresholds (MTL positivity 10.2–16.9%), had approximately three-fold higher odds of Aβ PET and pTau217 positivity than TSE 0-25% (ORs 2.90–3.46). 53.4% of intermediate Flortaucipir cases (TSE 25–50%) shifted to a higher MK6240 category, and 82.5% of moderately high Flortaucipir cases (50–75%) were classified as near-saturated (75–100%) by MK6240. Neither raw TSE nor raw SUVR was directly interchangeable across tracers, with systematic and proportional bias for both metrics (MTL Deming slope: TSE 1.29; SUVR 2.69). DISCUSSION: TSE showed stronger unadjusted associations than SUVR in selected region- and outcome-specific comparisons, supporting its potential as a complementary measure. Like SUVR, raw TSE values were not directly interchangeable between flortaucipir and MK6240, and tracer-specific calibration and validation are required before cross-tracer use.