Tau Imaging with 18F-MK6240 across the Alzheimer's Disease spectrum

Tau deposition plays a critical role over cognition and neurodegeneration in Alzheimers disease (AD). Recent generation tracers have high target to background ratios giving a wide dynamic range that may improve sensitivity for detection of low levels of tau (Pascoal, Shin et al. 2018). Building on previous evidence, this study aims to characterize the effects of tau deposition as assessed by 18F-MK6240, in a large cohort of patients across the AD disease spectrum. A total of 464 participants, enrolled in the AIBL-ADNeT study, underwent 18F-MK6240 tau PET, 18F-NAV4964 A{beta} PET, 3D structural MRI (hippocampal and whole-brain cortical volumes) and extensive neuropsychological evaluation. Participants included 266 cognitively unimpaired controls (CU), 112 patients with mild cognitive impairment (MCI), and 86 patients with probable AD dementia. Evaluation included the characterization of the pattern and degree of 18F-MK6240 tracer retention in each clinical group as well as assessment of the relationship between 18F-MK6240 and age, A{beta} imaging, brain volumetrics and cognition in each of the clinical groups. Standard uptake value ratios (SUVR) were estimated in four predefined composite regions of interest (ROIs), reflecting the stereotypical progression of tau pathology in the brain: 1. Mesial-temporal (Me), 2. Temporoparietal (Te), 3. Remainder of neocortex (R), 4. A temporal meta-region termed metaT+. 18F-MK6240 retention was higher in AD patients compared with all other diagnostic groups, with 18F-MK6240 distinguishing patients with AD from CU individuals, with the highest effect size obtained in the amygdala (Cohens d: 2.07), and Me (Cohens d: 1.99). When considering A{beta} status, 18F-MK6240 not only was able to distinguish between A{beta}+ AD patients and A{beta}- CU (Cohens d: 2.23), but also between A{beta}+ and A{beta}- CU (Cohens d: 1.32). In A{beta}- CU, 18F-MK6240 retention in Me showed a slow age-related increase, while 18F-MK6240 retention was higher in younger elderly A{beta}+ AD patients compared to their older counterparts. There was a sigmoidal relationship between subthreshold tau and A{beta}, providing evidence for a very slow but steady increase in subthreshold tau prior to a fast increase in cortical A{beta}. Moreover, a non-linear relationship between A{beta} and tau suggest that detectable cortical A{beta} precedes detectable cortical tau. While age was the main predictor of cognitive decline in CU, and A{beta} and hippocampal volume in MCI, the main predictor of cognitive decline in the AD group was tau. High tau was associated with faster cognitive decline and clinical progression in the CU and MCI groups. This large study provides further evidence that 18F-MK6240 discriminates CU from AD and, most importantly, A{beta}+ from A{beta}- CU individuals with high effect sizes, suggesting that 18F- MK6240 can detect lower tau levels than earlier tau tracers, crucial for early detection of tau deposition as well as tracking small tau changes over time. In conclusion, identification of regional cortical tau deposition has critical diagnostic and prognostic implications and should become a standard tool to identify individuals at risk, as well as outcome measure, in both anti- A{beta} and anti-tau trials.