Detection of tau spatial extent using MK6240 and flortaucipir PET

Tau PET enables in vivo quantification of neurofibrillary tangle spread, yet whether tau spatial extent (TSE) performs comparably across tracers remains unknown.

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.

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).

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.