Rates of regional tau accumulation in ageing and across the Alzheimer's disease continuum: an AIBL 18F-MK6240 PET study

Abstract

Background: Tau positron emission tomography (PET) imaging enables longitudinal observation of tau accumulation in Alzheimer's disease (AD). ¹⁸F-MK6240 is a high affinity tracer for the paired helical filaments of tau in AD, widely used in clinical trials, despite sparse longitudinal natural history data. We aimed to evaluate the natural history of tau accumulation, and the impact of disease stage and reference region on the magnitude and effect size of regional change.

Methods: One hundred and eighty-four participants: 89 cognitively unimpaired (CU) beta-amyloid negative (Aβ-), 44 CU Aβ+, 51 cognitively impaired Aβ+ (26 with mild cognitive impairment [MCI] and 25 with dementia) had follow-up ¹⁸F-MK6240 PET for one to four years (median 1.48). Regional standardised uptake value ratios (SUVR) were generated. Two reference regions were examined: cerebellar cortex and eroded subcortical white matter.

Findings: CU Aβ- participants had very low rates of tau accumulation in the mesial temporal lobe (MTL). In CU Aβ+, significantly higher rate of accumulation was seen in the MTL (particularly the amygdala), extending into the inferior temporal lobes. In MCI Aβ+, the rate of accumulation was greatest in the lateral temporal, parietal and lateral occipital cortex, and plateaued in the MTL. Accumulation was global in AD Aβ+, except for a plateau in the MTL. The eroded subcortical white matter reference region showed no significant advantage over the cerebellar cortex and appeared prone to spill-over in AD participants. Data fitting suggested approximately 15-20 years to accumulate tau to typical AD levels.

Interpretation: Tau accumulation occurs slowly. Rates vary according to brain region, disease stage and tend to plateau at high levels. Rates of tau accumulation are best measured in the MTL and inferior temporal cortex in preclinical AD and in large neocortical areas, in MCI and AD.

Funding: NHMRC; Cerveau Technologies.

Keywords: (18)F-MK6240; Alzheimer's disease; Longitudinal; Positron emission tomography (PET); Tau.

Fig. 1

Annual rate of ¹⁸F-MK6240 accumulation across the clinical groups (cerebellar cortex reference region). Vertex-based surface projections demonstrating the spatial distribution and rate of ¹⁸F-MK6240 accumulation (mean SUVR/year) for each clinical group, normalised to the cerebellar cortex. CU Aβ−: n = 89; CU Aβ+: n = 44; MCI Aβ+: n = 26; AD Aβ+: n = 25. Abbreviations: CU = cognitively unimpaired; CI = cognitively impaired; MCI = mild cognitive impairment; and AD = Alzheimer's disease dementia.

Fig. 2

Annual rate of tau SUVR change and annual percentage change in composite ROI. Boxplots showing annual tau SUVR change in composite ROI for the clinical groups, normalised to a) cerebellar cortex reference region; and b) eroded subcortical white matter reference region. Boxplots showing annual tau SUVR percentage change in composite ROI for the clinical groups normalised to c) cerebellar cortex reference region; and d) eroded subcortical white matter reference region. The red dashed vertical line represents zero change. Within the boxes, the line represents the median value. The whiskers extend from the 5th to the 95th percentile. CU Aβ−: n = 89; CU Aβ+: n = 44; MCI Aβ+: n = 26; AD Aβ+: n = 25. Abbreviations: CU = cognitively unimpaired; MCI = mild cognitive impairment; AD = Alzheimer's disease dementia.

Fig. 3

Spatiotemporal trajectory of tau accumulation.Fig. 3 shows the natural history of regional tau accumulation measured as ¹⁸F-MK6240 SUVR normalised to the cerebellar cortex reference region, as fitted from the data. The first three solid vertical lines represent mean CU Aβ− SUVR_Cb values for the composite ROI (Me: 0.89, Te: 1.02; R: 0.88). The next three solid vertical lines and the dashed horizontal lines represent the mean AD Aβ+ SUVR_Cb values for the composite ROI (Me: 1.90, Te: 2.74, R: 1.71). The dashed vertical lines and solid horizontal lines represent the threshold for abnormality (95th percentile of CU Aβ−). To reach the mean SUVR_Cb observed in AD from the mean SUVR_Cb observed in CU Aβ−, it takes approximately 16 years in Me, 17 years in Te, and 20 years in R. Abbreviations: Me = mesial temporal (green), Te = temporoparietal (red), and R = rest of neocortex (blue).