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Longitudinal change in CSF Tau and Aβ biomarkers for up to 48 months in ADNI

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Abstract

The dynamics of cerebrospinal fluid (CSF) tau and Aβ biomarkers over time in Alzheimer’s disease (AD) patients from prodromal pre-symptomatic to severe stages of dementia have not been clearly defined and recent studies, most of which are cross-sectional, present conflicting findings. To clarify this issue, we analyzed the longitudinal CSF tau and Aβ biomarker data from 142 of the AD Neuroimaging Initiative (ADNI) study subjects [18 AD, 74 mild cognitive impairment (MCI), and 50 cognitively normal subjects (CN)]. Yearly follow-up CSF collections and studies were conducted for up to 48 months (median = 36 months) for CSF Aβ1–42, phosphorylated tau (p-tau181), and total tau (t-tau). An unsupervised analysis of longitudinal measurements revealed that for Aβ1–42 and p-tau181 biomarkers there was a group of subjects with stable longitudinal CSF biomarkers measures and a group of subjects who showed a decrease (Aβ1–42, mean = −9.2 pg/ml/year) or increase (p-tau181, mean = 5.1 pg/ml/year) of these biomarker values. Low baseline Aβ1–42 values were associated with longitudinal increases in p-tau181. Conversely, high baseline p-tau181 values were not associated with changes in Aβ1–42 levels. When the subjects with normal baseline biomarkers and stable concentrations during follow-up were excluded, the expected time to reach abnormal CSF levels and the mean AD values was significantly shortened. Thus, our data demonstrate for the first time that there are distinct populations of ADNI subjects with abnormal longitudinal changes in CSF p-tau181 and Aβ1–42 levels, and our longitudinal results favor the hypothesis that Aβ1–42 changes precede p-tau181 changes.

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Acknowledgments

This study was supported in part by the NIH/NIZ (AG10124 and AG24904). JQT is the William Maul Measey-Truman G. Schnabel, Jr., Professor of Geriatric Medicine and Gerontology and JBT is supported in part by a Grant of the Alfonso Martín Escudero Foundation. We would like to thank Xiaoyan Han, M.S. for her help with the statistical programming. J.B.T., S.X.X., J.Q.T. and LMS have no conflicts of interest. Data collection and sharing for this project were funded by the Alzheimer’s Disease Neuroimaging Initiative (ADNI) (National Institutes of Health Grant U01 AG024904). ADNI is funded by the National Institute on Aging, the National Institute of Biomedical Imaging and Bioengineering, and through generous contributions from the following: Alzheimer’s Association; Alzheimer’s Drug Discovery Foundation; BioClinica, Inc.; Biogen Idec Inc.; Bristol-Myers Squibb Company; Eisai Inc.; Elan Pharmaceuticals, Inc.; Eli Lilly and Company; F. Hoffmann-La Roche Ltd and its affiliated company Genentech, Inc.; GE Healthcare; Innogenetics, N.V.; IXICO Ltd.; Janssen Alzheimer Immunotherapy Research & Development, LLC.; Johnson & Johnson Pharmaceutical Research & Development LLC.; Medpace, Inc.; Merck & Co., Inc.; Meso Scale Diagnostics, LLC.; NeuroRx Research; Novartis Pharmaceuticals Corporation; Pfizer Inc.; Piramal Imaging; Servier; Synarc Inc.; and Takeda Pharmaceutical Company. The Canadian Institutes of Health Research are providing funds to support ADNI clinical sites in Canada. Private sector contributions are Rev November 7, 2012 facilitated by the Foundation for the National Institutes of Health (http://www.fnih.org). The grantee organization is the Northern California Institute for Research and Education, and the study is coordinated by the Alzheimer’s Disease Cooperative Study at the University of California, San Diego. ADNI data are disseminated by the Laboratory for Neuro Imaging at the University of California, Los Angeles. This research was also supported by NIH Grants P30 AG010129 and K01 AG030514.

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Authors and Affiliations

  1. Department of Pathology and Laboratory Medicine, Institute on Aging, Center for Neurodegenerative Disease Research, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, 19104, USA

    Jon B. Toledo, John Q. Trojanowski & Leslie M. Shaw

  2. Department of Biostatistics and Epidemiology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, 19104, USA

    Sharon X. Xie

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  1. Jon B. Toledo
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  2. Sharon X. Xie
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Correspondence to Leslie M. Shaw.

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J. B. Toledo and S. X. Xie contributed equally to this paper.

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Toledo, J.B., Xie, S.X., Trojanowski, J.Q. et al. Longitudinal change in CSF Tau and Aβ biomarkers for up to 48 months in ADNI. Acta Neuropathol 126, 659–670 (2013). https://doi.org/10.1007/s00401-013-1151-4

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