Autosomal dominant Alzheimer’s disease (ADAD) provides a unique window into the earliest stages of β-amyloid (Aβ) pathogenesis. However, it remains unclear whether standard Aβ positron emission tomography (PET) semi-quantitative methods, including the standardized uptake value ratio (SUVR), Z-scores, and the Centiloid (CL) scale, which were developed primarily for sporadic Alzheimer’s disease (AD), can accurately capture ADAD-specific topographic patterns and Aβ burden in vivo. In this study, we aimed to compare the performance of these Aβ PET semi-quantitative metrics in asymptomatic carriers of ADAD mutations and evaluate their suitability for early detection and staging. Nineteen asymptomatic carriers of ADAD mutations and 21 cognitively normal (CN) controls underwent 18F-MK6240 hybrid PET/MR and 11C-PIB PET/CT imaging. Aβ PET images were analyzed using visual assessment (VA), SUVR, Z-score, and CL methods. Amyloid positivity was defined as abnormal increased 11C-PIB uptake in the striatum and/or cortical regions, with Z-score > 3 and CL > 21 and 30, respectively. ADAD carriers with marked 18F-MK6240 uptake in intracranial regions were categorized into tau positive (Tau +) group, while others were assigned to tau negative (Tau-) group. Based on visual assessment of tau-PET, 19 carriers were categorized into two groups: 10 into the Tau- group and 9 into the Tau+ group. The Tau+ group showed significantly higher Aβ burden across all cortical and subcortical regions. VA classified 3 participants in Tau- group and all 9 participants in the Tau+ group as Aβ positive. Their corresponding regions with Z-scores > 3 were found in the basal ganglia and early Aβ deposition regions. CLs of participants in Tau- group were all less than 21. VA and regional z-scores (> 3) were highly concordant, with both methods classifying all participants in the Tau+ group as Aβ-positive. Both the > 21 and > 30 CL thresholds classified only 5 of 9 (56%) participants in the Tau+ group as Aβ-positive; the remaining cases, whose focal Aβ deposition primarily localized to the striatum, were classified as Aβ-negative. Quantitative analysis also revealed that in the Tau+ group, Aβ burden in the caudate, putamen, and thalamus reached 100% positivity, whereas early cortical regions such as the angular gyrus and middle temporal cortex showed 75%-80% positivity. The CL scale is weighted toward the cortical regions, underestimating Aβ burden in ADAD, particularly in cases with a striatal-dominant pattern. The standard CL scale underestimates Aβ burden in ADAD due to limited sensitivity to striatal deposition. Regional Z-scores or striatum-weighted metrics should complement standard CL to improve diagnostic accuracy and trial eligibility assessment.
Zhou et al. (Tue,) studied this question.