Abstract Body

It is expected that tau imaging will provide a framework for staging and estimate Alzheimer’s disease (AD) progression. However, the off-target binding typically present in the first generation of tau imaging agents and the low tissue concentrations of tau typical from early Braak stages constitute a challenge for quantification of early pathophysiological phases AD. In fact, post-mortem Braak staging proposes that tau neurofibrillary tangle accumulation follows a stereotypical sequential pattern, beginning in the transentorhinal, spreading through the temporal, and then extra-temporal association and primary sensory cortices. Here we showed that high-sub-nanomolar imaging agents, due to their kinetic properties, identify individuals in the early stages of tau accumulation. We demonstrated these properties in a cohort of 301 individuals. Participants had imaging amyloid-beta PET with [¹⁸F]NAV4694, neurofibrillary tangles PET with [¹⁸F]MK-6240, magnetic resonance imaging, and clinical assessments. [¹⁸F]MK-6240 standardized uptake value ratio was quantified from 90-110 min. recapitulated the 6 hierarchical stages proposed by Braak in 98% of our population. No single region-of-interest accurately segregated individuals into the 6 Braak stages. [¹⁸F]MK-6240 SUVRs discriminated Alzheimer's disease from frontotemporal dementia patients (area under the curve = ~95-100%) with the highest accuracy in the transentorhinal, entorhinal, and hippocampal cortices. These results support that [¹⁸F]MK-6240 is suitable for staging preclinical and symptomatic AD. Tau positron emission tomography Braak staging using sub-nanomolar affinity tracers has the potential to be incorporated in the diagnosis and staging of living patients with AD.