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Cerebrospinal fluid A beta 1-40 peptides increase in Alzheimer's disease and are highly correlated with phospho-tau in control individuals

By Sylvain Lehmann, Julien Dumurgier, Xavier Ayrignac, Cecilia Marelli, Daniel Alcolea, Juan Fortea-Ormaechea, Eric Thouvenot, Constance Delaby, Christophe Hirtz, Jerome Vialaret, Nelly Ginestet, Elodie Bouaziz-Amar, Jean-Louis Laplanche, Pierre Labauge, Claire Paquet, Alberto Lleo, Audrey Gabelle, ADNI for the Alzheimer's Disease Neuroimaging Initiative

Posted 02 Jun 2020
medRxiv DOI: 10.1101/2020.06.02.20119578

Background: Amyloid pathology, which is one of the characteristics of Alzheimer's disease (AD), results from altered metabolism of the beta-amyloid peptide (A{beta}) in terms of synthesis, clearance or aggregation. A decrease in cerebrospinal fluid (CSF) level A{beta}1-42 is evident in AD, and the CSF ratio A{beta}40 /A{beta}40 has recently been identified as one of the most reliable diagnostic biomarkers of amyloid pathology. Variations in inter-individual levels of A{beta}1-40 in the CSF have been observed in the past, but their origins remain unclear. In addition, the variation of A{beta}40 in the context of AD studied in several studies has yielded conflicting results. Methods: Here, we analyzed the levels of A{beta}1-40 using multicenter data obtained on 2466 samples from six different cohorts in which CSF was collected under standardized protocols, centrifugation and storage conditions. Tau and p-tau(181) concentrations were measured using commercially available in vitro diagnostic immunoassays. Concentrations of CSF A{beta}1-42 and A{beta}1-40 were measured by ELISA, xMAP technology, chemiluminescence immunoassay (CLIA) and mass spectrometry. Statistical analyses were calculated for parametric and non-parametric comparisons, linear regression, correlation and odds ratios. The statistical tests were adjusted for the effects of covariates (age, in particular). Results: Regardless of the analysis method used and the cohorts, a slight but significant age-independent increase in the levels of A{beta}40 in CSF was observed in AD. We also found a strong positive correlation between the levels of A{beta}40 and p-tau(181) in CSF, particularly in control patients. Conclusions: These results indicate that an increase in the baseline level of amyloid peptides, which are associated with an increase in p-tau(181), may be a biological characteristic of AD. This confirms the potential therapeutic value of lowering the baseline levels of A{beta}40 which, being elevated, can be considered a risk factor for the disease.

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