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The nonlinear relationship between cerebrospinal fluid A beta(42) and tau in preclinical Alzheimer's disease

de Leon, MJ; Pirraglia, E; Osorio, RS; Glodzik, L; Saint-Louis, L; Kim, H-J; Fortea, J; ... Blennow, K; + view all (2018) The nonlinear relationship between cerebrospinal fluid A beta(42) and tau in preclinical Alzheimer's disease. PLoS One , 13 (2) , Article e0191240. 10.1371/journal.pone.0191240. Green open access

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Abstract

Cerebrospinal fluid (CSF) studies consistently show that CSF levels of amyloid-beta 1–42 (Aβ42) are reduced and tau levels increased prior to the onset of cognitive decline related to Alzheimer’s disease (AD). However, the preclinical prediction accuracy for low CSF Aβ42 levels, a surrogate for brain Aβ42 deposits, is not high. Moreover, the pathology data suggests a course initiated by tauopathy contradicting the contemporary clinical view of an Aβ initiated cascade. CSF Aβ42 and tau data from 3 normal aging cohorts (45–90 years) were combined to test both cross-sectional (n = 766) and longitudinal (n = 651) hypotheses: 1) that the relationship between CSF levels of Aβ42 and tau are not linear over the adult life-span; and 2) that non-linear models improve the prediction of cognitive decline. Supporting the hypotheses, the results showed that a u-shaped quadratic fit (Aβ2) best describes the relationship for CSF Aβ42 with CSF tau levels. Furthermore we found that the relationship between Aβ42 and tau changes with age—between 45 and 70 years there is a positive linear association, whereas between 71 and 90 years there is a negative linear association between Aβ42 and tau. The quadratic effect appears to be unique to Aβ42, as Aβ38 and Aβ40 showed only positive linear relationships with age and CSF tau. Importantly, we observed the prediction of cognitive decline was improved by considering both high and low levels of Aβ42. Overall, these data suggest an earlier preclinical stage than currently appreciated, marked by CSF elevations in tau and accompanied by either elevations or reductions in Aβ42. Future studies are needed to examine potential mechanisms such as failing CSF clearance as a common factor elevating CSF Aβxx analyte levels prior to Aβ42 deposition in brain.

Type: Article
Title: The nonlinear relationship between cerebrospinal fluid A beta(42) and tau in preclinical Alzheimer's disease
Open access status: An open access version is available from UCL Discovery
DOI: 10.1371/journal.pone.0191240
Publisher version: http://doi.org/10.1371/journal.pone.0191240
Language: English
Additional information: Copyright: © 2018 de Leon et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
URI: http://discovery.ucl.ac.uk/id/eprint/10051881
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