CSF beta-amyloid 1-42 - what are we measuring in Alzheimer's disease?

• Type of Material: Article
• Authors: William Hu, Emory University; Kelly D Watts, Emory University; Leslie M Shaw, University of Pennsylvania; Jennifer Christina Howell, Emory University; John Q Trojanowski, University of Pennsylvania; Sundeep Basra, Emory University; Jonathan D Glass, Emory University; James J Lah, Emory University; Allan I Levey, Emory University
• Language: English
• Date: 2015-02
• Publisher: Wiley Open Access: Creative Commons Attribution Non-Commercial No Derivatives
• Publication Version: Final Published Version
• Copyright Statement: © 2014 The Authors.
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1002/acn3.160
• Title of Journal or Parent Work: Annals of Clinical and Translational Neurology
• ISSN: 2328-9503
• Volume: 2
• Issue: 2
• Start Page: 131
• End Page: 139
• Grant/Funding Information: The study sponsors have no role in the study design; collection, analysis, and interpretation of data; writing the report; and the decision to submit the report for publication.; This study has been supported by the Viretta Brady Discovery Fund, Emory University Center for Neurodegenerative Diseases, and AG 016976 at Emory University, and by the ADNI grant R01 AG10124.
• Research Categories: Health Sciences, General; Health Sciences, Pathology

Abstract

Objective To characterize biological and technical factors which influence cerebrospinal fluid (CSF) Alzheimer's disease (AD) biomarker levels, including the presence of apolipoprotein E (APOE) ε4 allele, AD diagnosis, Aβ-binding proteins, sample processing, and preanalytical handling. Methods CSF was collected from 140 subjects with normal cognition, mild cognitive impairment, AD, and non-AD dementia. CSF levels of beta-amyloid 1–42 (Aβ42), total Tau (t-Tau), and Tau phosphorylated at threonine 181 (p-Tau181) were analyzed following the standard and modified protocols. CSF levels of apoJ, apoE, albumin, and α-synuclein were measured in a subgroup (n = 69), and their effects on measured AD biomarker levels were also determined in vitro using human CSF samples. Results CSF Aβ42 levels measured using the AD Neuro-imaging Initiative (ADNI) protocol (which we call suspended Aβ42 or susAβ) were lower than total measurable CSF Aβ42 in all groups, and on average represents 57% of the latter. Logistic regression analysis showed this proportion (% susAβ) to be directly correlated with CSF Aβ42 and apoJ levels, but inversely correlated with CSF t-Tau levels. Finally, we showed in vitro that increasing apoE and apoJ levels directly increased % susAβ. Conclusion CSF susAβ levels are influenced by biological and technical factors, and may represent a marker of Aβ susceptible to lipoprotein-mediated clearance. Clinical trials should include total measurable Aβ42 and susAβ to better inform outcomes.