High precision plasma Aβ42/Aβ40 ratio detects early amyloid deposition in non‐demented elderly adults

Abstract

AbstractBackgroundPlasma Aβ42/Aβ40 ratio measured by an immunoprecipitation and liquid chromatography–mass spectrometry assay showed high accordance with amyloid PET. However, it is still unclear about the risk factors related to plasma Aβ42/Aβ40, whether it can detect Aβ pathology earlier than Aβ PET, and how it relates to tau deposition, neurodegeneration and cognitive decline. In this study, we aim to investigate: 1) the risk factors related to plasma Aβ42/Aβ40; 2) the concordance and discordance of plasma Aβ42/Aβ40 and Aβ PET, and their associations with tau deposition at follow‐up and perspective changes of Aβ PET, neurodegeneration and cognition in cognitively unimpaired (CU) and mild cognitive impairment (MCI) elderly adults.MethodWe analyzed 181 (97 CU, 85 MCI) ADNI participants with plasma Aβ42/Aβ40, Aβ PET, white matter hyperintensities (WMH), vascular factors, adjusted hippocampal volume (aHCV) measured by structural MRI, 18F‐fluorodeoxyglucose (FDG) PET and memory score obtained within one year. The associations of plasma Aβ42/Aβ40 with age, sex, APOE‐ε4 status, vascular risk factors were tested using Pearson’s correlation or Mann‐Whitney U test. Participants were classified into Plasma±/PET± groups according to the thresholds of plasma Aβ42/Aβ40 and Aβ PET (Fig.2A). Longitudinal changes of Aβ accumulation, aHCV, FDG PET and cognition, and tau PET measured at a mean of 5.32±1.24 years later were compared among different Plasma±/PET± groups.ResultWe found older age, APOE‐ε4 carrier and greater WMH burden (Fig.1) were significantly related to reduced plasma Aβ42/Aβ40. Plasma Aβ42/Aβ40 may become abnormal earlier than Aβ PET. Plasma+/PET‐ individuals were accumulating Aβ burden in early‐affected brain regions (Fig. 2), had no evidence of tau deposition, neurodegeneration and cognitive decline at follow‐up (Fig. 3), suggesting Plasma+/PET‐ individuals are very likely in the very early stage of Alzheimer’s disease (AD).ConclusionIn summary, our results suggest that age, APOE4 carrier and white matter lesion may be related to lower plasma Aβ42/Aβ40. Individuals with abnormal plasma Aβ42/Aβ40 but normal Aβ PET may be at early stage of Aβ pathology, are significantly accumulating Aβ in AD typical cortical regions. These findings may provide useful reference for screening Aβ+ participants by using plasma Aβ42/Aβ40.