Comparative performance of semi-quantitative methods for amyloid deposition in preclinical autosomal dominant Alzheimer’s disease

BACKGROUND: 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. METHODS: F-MK6240 uptake in intracranial regions were categorized into tau positive (Tau +) group, while others were assigned to tau negative (Tau-) group. RESULTS: 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. CONCLUSIONS: 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.