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

Tau deposition plays a critical role over cognition and neurodegeneration in Alzheimer’s 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][1]). 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 Aβ 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, Aβ 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 (Cohen’s d : 2.07), and Me (Cohen’s d : 1.99). When considering Aβ status, 18F-MK6240 not only was able to distinguish between Aβ+ AD patients and Aβ- CU (Cohen’s d : 2.23), but also between Aβ+ and Aβ- CU (Cohen’s d : 1.32). In Aβ- CU, 18F-MK6240 retention in Me showed a slow age-related increase, while 18F-MK6240 retention was higher in younger elderly Aβ+ AD patients compared to their older counterparts. There was a sigmoidal relationship between subthreshold tau and Aβ, providing evidence for a very slow but steady increase in subthreshold tau prior to a fast increase in cortical Aβ. Moreover, a non-linear relationship between Aβ and tau suggest that detectable cortical Aβ precedes detectable cortical tau. While age was the main predictor of cognitive decline in CU, and Aβ 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, Aβ+ from Aβ- 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- Aβ and anti-tau trials. ### Competing Interest Statement Christopher C. Rowe has received research grants from NHMRC, Enigma Australia, Biogen, Eisai and Abbvie. He is on the scientific advisory board for Cerveau Technologies and has consulted for Prothena, Eisai, Roche, and Biogen Australia. Victor Villemagne is and has been a consultant or paid speaker at sponsored conference sessions for Eli Lilly, Life Molecular Imaging, GE Healthcare, IXICO, Abbvie, Lundbeck, Shanghai Green Valley Pharmaceutical Co Ltd, and Hoffmann La Roche. The other authors did not report any conflict of interest. ### Funding Statement The study was supported in part by National Health Medical Research Council (NHMRC) of Australia grants APP1132604, APP1140853 and APP1152623. A research grant was also provided by Cerveau Technologies. The funding sources had no input into the design of this study, the analysis of data, or writing of the manuscript. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The study was approved by the Austin Health Human Research Ethics Committee. Written informed consent was obtained from participants and/or from the next of kin or carer for the participants with dementia, prior to participation. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes Anonymized data may be shared upon request to the corresponding author from a qualified investigator, subject to restrictions according to participant consent and data protection legislation. [1]: #ref-40