When Is Amyloid Really Cleared? Substantial Discordance Between Centiloid Quantification and Visual Reads of Amyloid PET after Amyloid-Targeting Therapy

Amyloid-targeting therapies (ATTs) substantially reduce amyloid PET signal and slow clinical decline in early symptomatic Alzheimer disease. As ATTs enter clinical practice, PET may assess target engagement and guide treatment management, but there is no consensus on how to measure treatment-related amyloid clearance (TRAC). We compared Centiloid quantification across pipelines and visual reads for interpreting pre- and post-ATT amyloid PET. Methods: We analyzed 18F-florbetapir or 18F-florbetaben PET from 101 patients treated with lecanemab or donanemab: 88 pre-ATT and 54 post-ATT scans, including 41 paired scans. Centiloids were derived using FDA-cleared MIMneuro and two research pipelines (rPOP, CapAIBL) and compared using intraclass correlation coefficients (ICC). Clearance rates were estimated using linear mixed-effects models. Full TRAC was defined on post-ATT scans quantitatively (<11 Centiloids) or based on visual interpretation by three expert readers. Results: Treated patients were 74+/-7 years old; 57% were female, 59% were apolipoprotein E4 carriers, and 78% had mild cognitive impairment (22% mild dementia). Centiloid agreement between pipelines was equally high pre- and post-ATT (both ICCs=0.90). Among paired scans (mean treatment duration, 16.7 +/- 4.6 months), clearance estimates were similar across pipelines and greater with donanemab (n=15 patients; between -62 and -60 Centiloids/year depending on the pipeline) than lecanemab (n=26; -38 to -36 Centiloids/year; all Ps<0.005). Among 54 post-ATT scans, between 44% and 57% were <11 Centiloids depending on pipeline, with 20 (37%) meeting this criterion across all three pipelines. In contrast, only 11% to 19% were visually negative across readers, with 4 (7%) unanimously read as negative. Of the 20 post-ATT scans <11 Centiloids across all pipelines, 13 (65%) were considered positive by all readers, commonly with residual occipital binding. Conclusion: Centiloid quantification was robust across pipelines before and after ATT initiation, yielding clearance rates consistent with clinical trials. However, quantitative and visual assessments were markedly discordant after ATT, with an unusually high proportion of scans <11 Centiloids remaining visually positive, warranting cautious interpretation of post-ATT Centiloid values. Larger studies should assess the clinical relevance of these findings and further develop robust approaches to establish full TRAC.