• Florbetapir spatial extent replicates PiB findings in preclinical AD. • Spatial extent detects early amyloid-β spread below SUVR thresholds. • EXT predicts early medial temporal tau accumulation and plasma pTau217 levels. • Spatial extent improves early detection and could improve trial enrichment in AD. Prevention of Alzheimer’s disease (AD) requires biomarkers sensitive to the earliest amyloid - β (Aβ) deposits . To characterize performance of a recently-developed Aβ-PET spatial extent metric (EXT) for early Aβ detection using 18 F-florbetapir (FBP)-PET, evaluating its sensitivity, reliability, and associations with plasma pTau217, tau-PET, and cognition . Longitudinal study with up to 5.5 years of PET, plasma and cognitive measures. The Anti-Amyloid Treatment in Asymptomatic Alzheimer’s disease (A4) Study and its companion screen-fail study Longitudinal Evaluation of Amyloid and Neurodegeneration Risk (LEARN) conducted across 67 international sites. 1118 cognitively unimpaired older adults from the A4 placebo arm and LEARN. EXT (% of neocortex above region-specific thresholds), global Aβ SUVR, plasma pTau217, medial temporal (MTL) and temporal neocortical (nTEMP) tau-PET SUVR, and Preclinical Alzheimer Cognitive Composite (PACC). EXT showed high cross-sectional reliability and longitudinal stability. Using EXT reclassified 21.4% of SUVR-participants from Aβ− to Aβ+ and predicted who would progress to SUVR+ 5.5 years later with 83% sensitivity and 94% specificity. In SUVR− individuals, higher pTau217 associated with greater SUVR only within EXT+ individuals. Baseline EXT outperformed SUVR in predicting MTL tau proliferation. For neocortical tau SUVR and PACC change, EXT was the better predictor in earlier Aβ stages (while Aβ spread) while SUVR was superior later (after Aβ was widespread). EXT is a robust, generalizable PET metric that detects Aβ before global positivity and early Aβ-related changes in tau and cognition, supporting its relevance for trial enrichment and early therapeutic monitoring in AD prevention trials.
Thibault et al. (Fri,) studied this question.