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Correspondence: william.hu@emory.edu; Email: umesh.gangishetti@emory.edu

Authors’ contributions: UG, RJP, LMS, JCM, JQT, AMF, SEA, and WTH were responsible for conception and design of the study; UG, JCH, RJP, NL, KDW, AK, MG, DAW, LMS, JCM, JQT, AMF, SEA, and WTH were responsible for acquisition, analysis, and interpretation of data; UG, JCH, JQT, AMF, SEA, and WTH were responsible for drafting the manuscript and revising it critically for important intellectual content.

All authors read and approved the final manuscript.

Acknowledgements: The authors wish to acknowledge Allan I. Levey, MD, PhD, James J. Lah, MD, PhD, David M. Holtzman, MD, Jason H. Karlawish, MD, and Vivianna Van Deerlin, MD, PhD, and the National Alzheimer’s Coordinating Center for funding, collecting data, and general support.

Competing interests: LMS has received personal compensation for activities with Roche Diagnostics which produces CSF amyloid and tau assays.

AMF is on the Scientific Advisory Boards for Roche Diagnostics which produces CSF amyloid and tau assays.

WTH consults for ViveBio, LLC., which manufactures lumbar puncture trays; has a patent (assignee: Emory University) on the use of CSF p/t-Tau ratio in the evaluation of FTLD; has received research support from Fujirebio USA and Avid Pharmaceuticals; has received travel support from Hoffman La Roche and Abbvie.

The remaining authors declare that they have no competing interests.

Subjects:

Research Funding:

This work was supported by the National Institutes of Health (AG43885, AG42856, AG25688, AG10124, AG17586, AG05681, AG26276, AG03991, AG16976).

Keywords:

  • Biomarkers
  • Fatty acid binding protein
  • Interleukin-10
  • Mild cognitive impairment
  • Neurofilament light chain

Non-beta-amyloid/tau cerebrospinal fluid markers inform staging and progression in Alzheimer’s disease

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Journal Title:

Alzheimer's Research and Therapy

Volume:

Volume 10, Number 98

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Type of Work:

Article | Final Publisher PDF

Abstract:

Background Alzheimer’s disease (AD) is a complex neurodegenerative disorder characterized by neuropathologic changes involving beta-amyloid (Aβ), tau, neuronal loss, and other associated biological events. While levels of cerebrospinal fluid (CSF) Aβ and tau peptides have enhanced the antemortem detection of AD-specific changes, these two markers poorly reflect the severity of cognitive and functional deficits in people with altered Aβ and tau levels. While multiple previous studies identified non-Aβ, non-tau proteins as candidate neurodegenerative markers to inform the A/T/N biomarker scheme of AD, few have advanced beyond association with clinical AD diagnosis. Here we analyzed nine promising neurodegenerative markers in a three-centered cohort using independent assays to identify candidates most likely to complement Aβ and tau in the A/T/N framework. Methods CSF samples from 125 subjects recruited at the three centers were exchanged such that each of the nine previously identified biomarkers can be measured at one of the three centers. Subjects were classified according to cognitive status and CSF AD biomarker profiles as having normal cognition and normal CSF (n = 31), normal cognition and CSF consistent with AD (n = 13), mild cognitive impairment and normal CSF (n = 13), mild cognitive impairment with CSF consistent with AD (n = 23), AD dementia (n = 32; CSF consistent with AD), and other non-AD dementia (n = 13; CSF not consistent with AD). Results Three biomarkers were identified to differ among the AD stages, including neurofilament light chain (NfL; p < 0.001), fatty acid binding protein 3 (Fabp3; p < 0.001), and interleukin (IL)-10 (p = 0.033). Increased NfL levels were most strongly associated with the dementia stage of AD, but increased Fabp3 levels were more sensitive to milder AD stages and correlated with both CSF tau markers. IL-10 levels did not correlate with tau biomarkers, but were associated with rates of longitudinal cognitive decline in mild cognitive impairment due to AD (p = 0.006). Prefreezing centrifugation did not influence measured CSF biomarker levels. Conclusion CSF proteins associated with AD clinical stages and progression can complement Aβ and tau markers to inform neurodegeneration. A validated panel inclusive of multiple biomarker features (etiology, stage, progression) can improve AD phenotyping along the A/T/N framework.

Copyright information:

© The Author(s). 2018

This is an Open Access work distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/).
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