Amyloid-PET pipeline choice influences classification of preclinical Alzheimer's disease

BACKGROUND: Quantitative amyloid-beta (A{beta})-PET is increasingly used in AD prevention trials. Although the Centiloid (CL) framework provides a common scale, variability persists across processing pipelines, including differences in template/native space, partial volume correction (PVC), and reference region. These choices may influence cut-points, and in turn positivity rates, as well as longitudinal accumulation rates. We examined cut-point estimates and inter-pipeline discordance in a community cohort where many are expected to have early A{beta} deposition. METHODS: We analysed [18F]florbetapir PET/MR data from predominantly cognitively unimpaired (~95%) individuals aged ~71 years at baseline (n=433) and at follow-up (n=328; ~2.4-year interval) in Insight 46 (1946 British birth cohort). Centiloids were derived using the standard pipeline and ten in-house pipelines employing alternative reference regions and PVC in native space. Gaussian mixture modelling estimated cut-points with bootstrapped uncertainty. We assessed A{beta}-discordance across pipelines as a function of standard CLs and examined follow-up CSF A{beta}42/A{beta}40 (n=120) and PET in individuals with discordant baseline classifications. RESULTS: Baseline cut-points were 10-23 CL across pipelines, classifying 16-25% as A{beta}-positive. Reliable accumulation cut-points were 3.5-6 CL/year, identifying 16-22% as accumulators. Uncertainty varied across pipelines. At baseline, 18% were discordant across PET measures, predominantly between 11-35 standard CLs. The discordant group showed higher A{beta}-PET accumulation and lower CSF A{beta}42/A{beta}40 than concordant negatives. CONCLUSIONS: Disagreement between A{beta}-PET methods was highest between 11-35 standard Centiloids and was frequently associated with accumulating A{beta}. These findings highlight the importance of considering cut-point uncertainty and methodological influences when interpreting early-stage amyloidosis.