Newer Tau-PET Tracer MK6240 Detects Behavioral Changes in Early Alzheimer's More Precisely

Mild behavioral impairment (MBI) describes new, persistent late-life changes in motivation, mood, impulse control, social behavior, or perception that appear before dementia. It is increasingly viewed as an early marker of Alzheimer's disease (AD). It predicts progression and neuropathologically confirmed AD, and it can be screened cheaply with an informant-rated checklist. Yet findings linking MBI to tau PET imaging have been inconsistent, and it has been unclear whether the choice of tracer explains the variability.

The researchers drew on the TRIAD cohort at McGill University and studied 110 adults aged 50 and older (mean age 67.1; 64.5% women). Participants were 52 cognitively unimpaired (CU) amyloid-negative controls, 27 CU amyloid-positive individuals (preclinical AD), and 31 amyloid-positive people with mild cognitive impairment (prodromal AD). Each had head-to-head scans with first-generation [18F]Flortaucipir and second-generation [18F]MK6240, acquired about 24 days apart on average. Informants completed the 34-item MBI Checklist (MBI-C; 0-102). Analyses covered voxel-wise regression, Braak-region correlations, PET-based Braak staging, ROC curves, and tracer-positivity groups.

At the voxel level, MK6240 captured more of the brain showing an association with MBI severity: 5.18% of voxels versus 2.81% for Flortaucipir (p<0.001). Only 1.75% of voxels were significant for both, and 3.43% were unique to MK6240 versus 1.06% unique to Flortaucipir. Associations clustered in the medial temporal lobes, with extension to lateral temporal, temporoparietal, and posterior temporo-occipital cortex, plus smaller frontal clusters.

In regional analyses, higher total MBI-C, decreased motivation, and affective dysregulation correlated with tau in all Braak regions for both tracers. Social inappropriateness correlated across all Braak regions with MK6240 but only in Braak I-II with Flortaucipir. Abnormal thoughts and perception correlated only with MK6240 in Braak III-IV. MK6240 correlations were significantly stronger in Braak III-IV for those two domains. MBI-C scores rose across PET-derived Braak stages for both tracers, with stages III-IV and V-VI significantly higher than stage 0. Affective dysregulation climbed most steeply. Within diagnostic subgroups, significant associations appeared only in amyloid-positive groups, chiefly affective symptoms with MK6240.

For discriminating clinically defined MBI, Braak I-II measures from both tracers performed similarly (AUC 0.78-0.80). In the temporal meta-ROI, MK6240 spatial extent of tau outperformed its SUVR (AUC 0.78 vs 0.69, p<0.05). Tau positivity was associated with a higher frequency of MBI. Individuals positive for MK6240 but negative for Flortaucipir had greater MBI burden than those negative for both. This suggests MK6240 is more sensitive to tau pathology related to behavioral symptoms.

Important caveats apply. After adjusting for global amyloid burden (centiloid), most regional associations were no longer significant. Only affective dysregulation with MK6240 in Braak I-II and V-VI remained. Some subgroup findings rest on very few symptomatic people; for example, only 2 of 27 CU amyloid-positive participants had decreased motivation. The design is cross-sectional, so it cannot show whether tracer choice changes prediction of future behavioral decline. Longitudinal work is needed.