Characteristics of discordance between amyloid positron emission tomography and plasma amyloid-β 42/40 positivity

Various plasma biomarkers for amyloid-β (Aβ) have shown high predictability of amyloid PET positivity. However, the characteristics of discordance between amyloid PET and plasma Aβ42/40 positivity are poorly understood. Thorough interpretation of discordant cases is vital as Aβ plasma biomarker is imminent to integrate into clinical guidelines. We aimed to determine the characteristics of discordant groups between amyloid PET and plasma Aβ42/40 positivity, and inter-assays variability depending on plasma assays. We compared tau burden measured by PET, brain volume assessed by MRI, cross-sectional cognitive function, longitudinal cognitive decline and polygenic risk score (PRS) between PET/plasma groups (PET-/plasma-, PET-/plasma+, PET+/plasma-, PET+/plasma+) using Alzheimer's Disease Neuroimaging Initiative database. Additionally, we investigated inter-assays variability between immunoprecipitation followed by mass spectrometry method developed at Washington University (IP-MS-WashU) and Elecsys immunoassay from Roche (IA-Elc). PET+/plasma+ was significantly associated with higher tau burden assessed by PET in entorhinal, Braak III/IV, and Braak V/VI regions, and with decreased volume of hippocampal and precuneus regions compared to PET-/plasma-. PET+/plasma+ showed poor performances in global cognition, memory, executive and daily-life function, and rapid cognitive decline. PET+/plasma+ was related to high PRS. The PET-/plasma+ showed intermediate changes between PET-/plasma- and PET+/plasma+ in terms of tau burden, hippocampal and precuneus volume, cross-sectional and longitudinal cognition, and PRS. PET+/plasma- represented heterogeneous characteristics with most prominent variability depending on plasma assays. Moreover, IP-MS-WashU showed more linear association between amyloid PET standardized uptake value ratio and plasma Aβ42/40 than IA-Elc. IA-Elc showed more plasma Aβ42/40 positivity in the amyloid PET-negative stage than IP-MS-WashU. Characteristics of PET-/plasma+ support plasma biomarkers as early biomarker of amyloidopathy prior to amyloid PET. Various plasma biomarker assays might be applied distinctively to detect different target subjects or disease stages.