Impact of disease stage and reference region selection on longitudinal tau ¹⁸F‐MK6240 PET in Alzheimer’s disease

Abstract Background Tau PET imaging enables prospective longitudinal observation of the rate and location of tau accumulation in Alzheimer’s disease (AD). 18 F‐MK6240 is a newer, high affinity tracer for the paired helical filaments of tau in AD. It is widely used in clinical trials, despite sparse longitudinal natural history data. We aimed to evaluate the impact of two reference regions on the magnitude and effect size of regional change. Method One hundred and fifty‐eight participants: 83 Aβ‐ cognitively unimpaired (CU), 37 Aβ+ CU, 19 Aβ+ MCI, 19 Aβ+ AD had annual 18 F‐MK6240 PET imaging for a mean of 1.6 years. Standardized uptake value ratios (SUVR) were generated for three in‐house composite ROI: mesial temporal (Me), temporoparietal (Te), and rest of neocortex (R), and a Free‐Surfer derived meta‐temporal (MT) ROI. Two reference regions were examined: cerebellar cortex (SUVRcb) and eroded subcortical white matter (SUVRwm). Result Figure 1 shows the annual rate of tau SUVR change in composite ROI. In Aβ+ CU, tau accumulation was greatest in Me (2.8‐3.2%/ year) (vs Aβ‐ CU, Cohen’s d = 0.30 SUVRcb, 0.24 SUVRwm) and MT (3.2‐3.6%/year) (vs Aβ‐ CU, d = 0.36 SUVRcb, 0.31 SUVRwm). In Aβ+ MCI, tau accumulation was greatest in Te (2.3‐3.7%/year) (vs Aβ‐ CU, d = 0.34 SUVRcb, 0.41 SUVRwm). In Aβ+ AD, greatest increase was in Te and R, with a decrease in Me. In Aβ+ AD, SUVRcb showed marginally greater increase in these regions (e.g. 3.8%/year compared to 2.68%/year SUVRwm in R) (vs Aβ‐ CU, d = 0.60 SUVRcb, 0.27 SUVRwm). In the young Aβ+ AD dementia group, spill‐over from adjacent high cortical binding or an increase in white matter binding elevates signal in the reference region. Conclusion The rate of tau accumulation varies according to brain region and baseline tau. Change is greatest in the MTL in preclinical AD, in the MTL and lateral temporal cortex in MCI, and Braak V‐VI regions in AD dementia. The PET measured change is greater and less variable using an eroded white matter reference region, except in AD dementia, where spill‐over from adjacent high cortical binding or increase in white matter binding elevates the reference region.