In Vivo [18F]MK6240 PET Reveals Atypical Patterns of Early Tau Deposition and Evidence for Primary Age-Related Tauopathy in Community-Residing Adults

<h3>BACKGROUND AND PURPOSE:</h3> [18F]MK-6240, a second-generation tau PET tracer, enables in vivo detection of tau neurofibrillary tangles—one of the key pathologic hallmarks of Alzheimer’s disease (AD). Building on prior work demonstrating the utility of [18F]MK-6240 for in vivo Braak staging, this study assessed the frequency of typical and atypical tau deposition patterns in a cognitively unimpaired, community-residing cohort and associations with early memory changes. <h3>MATERIALS AND METHODS:</h3> One hundred seventy-three older adults (aged 69 +/- 5.7 years, 49% female) were recruited prospectively from the community to undergo [18F]MK-6240 tau PET, [18F]florbetaben amyloid PET, and clinical and neuropsychological evaluations. Images were analyzed qualitatively and quantitatively to determine amyloid and tau positivity, and participants were subsequently classified according to Braak stage. Associations with cognitive measures were assessed using linear regression models. <h3>RESULTS:</h3> Fifty-nine participants (34%) were found to be tau positive on PET: 32 were Braak stages I-II, 7 Braak stages III-IV, 19 Braak stages V-VI, and 1 had tau localized to the right thalamus. Notably, thirty participants (17%) were tau positive on PET but amyloid negative, suggestive of primary age-related tauopathy. Five had atypical tau deposition in cortical/subcortical regions without deposition in the medial temporal lobe, a departure from typical Braak staging, suggestive of hippocampal-sparing AD. Amyloid-positive, tau-positive participants had slightly lower cognition on the Montreal Cognitive Assessment (p=0.02) and Craft Story delayed recall (p=0.03). Amyloid-negative, tau-positive participants had lower Craft Story immediate recall scores (p=0.03). <h3>CONCLUSION:</h3> A significant proportion of older adults in the community have tau deposition in the brain, including those who are amyloid negative on PET, allowing for a critical therapeutic window before symptoms onset. Tau deposition patterns are heterogeneous and can deviate from traditional Braak staging, even in the preclinical stage, which underscores the need for an individualized, spatially-based approach to disease monitoring.