Temporal association patterns and dynamics of amyloid-β and tau in Alzheimer's disease

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Title: Temporal association patterns and dynamics of amyloid-β and tau in Alzheimer's disease
Author(s): Ower, AK
Hadjichrysanthou, C
Gras, L
Goudsmit, J
Anderson, RM
De Wolf, F
Alzheimer’s Disease Neuroimaging Initiative
Item Type: Journal Article
Abstract: The elusive relationship between underlying pathology and clinical disease hampers diagnosis of Alzheimer's disease (AD) and preventative intervention development. We seek to understand the relationship between two classical AD biomarkers, amyloid-β1-42 (Aβ1-42) and total-tau (t-tau), and define their trajectories across disease development, as defined by disease onset at diagnosis of mild cognitive impairment (MCI). Using longitudinal data from the Alzheimer's Disease Neuroimaging Initiative (ADNI), we performed a correlation analysis of biomarkers CSF Aβ1-42 and t-tau, and longitudinal quantile analysis. Using a mixed effects model, with MCI onset as an anchor, we develop linear trajectories to describe the rate of change across disease development. These trajectories were extended through the incorporation of data from cognitively normal, healthy adults (aged 20-62 years) from the literature, to fit sigmoid curves by means of non-linear least squares estimators, to create curves encompassing the 50 years prior to MCI onset. A strong right-angled relationship between the biomarkers Aβ1-42 and t-tau is detected, implying a highly non-linear relationship. The rate of change of Aβ1-42 is correlated with the baseline concentration per quantile, reflecting a reduction in the rate of loss across disease within subjects. Regression models reveal significant amyloid loss relative to MCI onset (- 2.35 pg/mL/year), compared to minimal loss relative to AD onset (- 0.97 pg/mL/year). Tau accumulates consistently relative to MCI and AD onset, (2.05 pg/mL/year) and (2.46 pg/mL/year), respectively. The fitted amyloid curve shows peak loss of amyloid 8.06 years prior to MCI diagnosis, while t-tau exhibits peak accumulation 14.17 years following MCI diagnosis, with the upper limit not yet reached 30 years post diagnosis. Biomarker trajectories aid unbiased, objective assessment of disease progression. Quantitative trajectories are likely to be of use in clinical trial design, as they allow for a more detailed insight into the effectiveness of treatments designed to delay development of biological disease.
Publication Date: 8-Jul-2018
Date of Acceptance: 7-Oct-2017
URI: http://hdl.handle.net/10044/1/54086
DOI: https://dx.doi.org/10.1007/s10654-017-0326-z
ISSN: 0393-2990
Publisher: Springer Verlag
Start Page: 657
End Page: 666
Journal / Book Title: European Journal of Epidemiology
Volume: 33
Issue: 7
Copyright Statement: © The Author(s) 2017. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.
Copyright Statement: © The Author(s) 2017. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.
Keywords: Alzheimer’s disease
Biomarkers
Incubation period
Alzheimer’s Disease Neuroimaging Initiative
Alzheimer’s disease
Biomarkers
Incubation period
1117 Public Health And Health Services
Epidemiology
Publication Status: Published
Online Publication Date: 2017-10-25
Appears in Collections:Faculty of Medicine
Epidemiology, Public Health and Primary Care



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