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Abstract: Objective: To better understand the seemingly contradictory plasma β-amyloid (Aβ) results in Alzheimer's disease (AD) patients by using a newly developed plasma Aβ assay, the INNO-BIA plasma Aβ forms, in a multicenter study. Methods: A combined retrospective analysis of plasma Aβ isoforms on mild cognitive impairment (MCI) from three large cross-sectional studies involving 643 samples from the participating German and Swedish centers. Results: Detection modules based on two different amino (N)-terminal specific Aβ monoclonal antibodies demonstrated that Aβ in plasma could be reliable quantified using a sandwich immunoassay technology with high precision, even for low Aβ42 plasma concentrations. Aβ40 and Aβ42 concentrations varied consistently with the ApoE genotype, while the Aβ42/Aβ40 ratio did not. Irrespective of the decrease of the Aβ42/Aβ40 ratio with age and MMSE, this parameter was strongly associated with AD, as defined in this study by elevated hyperphosphorylated (P-tau181P) levels in cerebrospinal fluid (CSF). Conclusion: A highly robust assay for repeatedly measuring Aβ forms in plasma such as INNO-BIA plasma Aβ forms might be a useful tool in a future risk assessment of AD.
Introduction
For prognostic and diagnostic purposes, as well as optimizing drug development, there is considerable interest relating biomarker information to the (future) event of Alzheimer's disease (AD) diagnosis. To this end, obtained from different body fluids have been studied. highly promising prognostic value has been observed cerebrospinal fluid (CSF) (1-4) the results for plasma A seem contradictory. Differing results may well be related assay configuration since antibodies are known to different epitopes or conformational forms of Aβ (5, 6), could be related to analytical assay performance, in particular the low concentrations of Aβ42 circulating in plasma. Apart from assay-related issues, disease-related factors could play an obfuscating role (7-9). Indeed, two recent studies using a new multiparameter assay format, INNO-BIA plasma Aβ forms, report seemingly divergent results. A first study concentrating on follow-up of MCI patients converting to AD showed no significant differences in Aß plasma levels (10), while in one of the largest MCI follow-up studies (11) in which also early dementia cases were included, highly significant reductions in the plasma Aβ42/Aβ40 ratio and in Aβ42 levels were reported. A major assumption underlying the methodology used in these studies is that (i) the biomarker level...