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PLoS One. 2018 Feb 7;13(2):e0191240. doi: 10.1371/journal.pone.0191240. eCollection 2018.

The nonlinear relationship between cerebrospinal fluid Aβ42 and tau in preclinical Alzheimer's disease.

Author information

1
Department of Psychiatry, Center for Brain Health, NYU Medical Center, New York, New York, United States of America.
2
Department of Population Health, Division of Biostatistics, NYU Medical Center, New York, New York, United States of America.
3
Nathan Kline Institute for Psychiatric Research, Orangeburg, New York, United States of America.
4
Department of Radiology, NYU Medical Center, New York, New York, United States of America.
5
Lennox Hill Radiology, New York, New York, United States of America.
6
Department of Neurology, Memory Unit, Hanyang University, Seoul, Korea.
7
Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain.
8
Sahlgrenska University Hospital, University of Gothenburg, Mölndal, Sweden.
9
Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry, the Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden.
10
Department of Molecular Neuroscience, UCL Institute of Neurology, London, United Kingdom.
11
UK Dementia Research Institute, London, United Kingdom.

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.

PMID:
29415068
PMCID:
PMC5802432
DOI:
10.1371/journal.pone.0191240
[Indexed for MEDLINE]
Free PMC Article

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