Cerebrospinal Fluid Sphingomyelins in Alzheimer’s Disease, Neurodegeneration, and Neuroinflammation1

Author:

Morrow Autumn1,Panyard Daniel J.2,Deming Yuetiva K.134,Jonaitis Erin35,Dong Ruocheng1,Vasiljevic Eva16,Betthauser Tobey J.34,Kollmorgen Gwendlyn7,Suridjan Ivonne8,Bayfield Anna7,Van Hulle Carol A.34,Zetterberg Henrik910111213,Blennow Kaj910,Carlsson Cynthia M.3414,Asthana Sanjay3414,Johnson Sterling C.3414,Engelman Corinne D.1

Affiliation:

1. Department of Population Health Sciences, University of Wisconsin-Madison, Madison, WI, USA

2. Department of Genetics, School of Medicine, Stanford University, Stanford, CA, USA

3. Wisconsin Alzheimer’s Disease Research Center, University of Wisconsin-Madison, Madison, WI, USA

4. Department of Medicine, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, USA

5. Wisconsin Alzheimer’s Institute, UW School of Medicine and Public Health, Madison, WI, USA

6. Center for Demography of Health and Aging, University of Wisconsin-Madison, Madison, WI, USA

7. Roche Diagnostics GmbH, Penzberg, Germany

8. Roche Diagnostics International Ltd, Rotkreuz, Switzerland

9. Institute of Neuroscience and Physiology, The Sahlgrenska Academy at University of Gothenburg, Mölndal, Sweden

10. Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden

11. United Kingdom Dementia Research Institute at UCL, London, United Kingdom

12. Department of Neurodegenerative Disease, UCL Institute of Neurology, London, United Kingdom

13. Hong Kong Center for Neurodegenerative Diseases, Hong Kong, China

14. William S. Middleton Memorial Veterans Hospital, 2500 Overlook Terrace, Madison, WI, USA

Abstract

Background: Sphingomyelin (SM) levels have been associated with Alzheimer’s disease (AD), but the association direction has been inconsistent and research on cerebrospinal fluid (CSF) SMs has been limited by sample size, breadth of SMs examined, and diversity of biomarkers available. Objective: Here, we seek to build on our understanding of the role of SM metabolites in AD by studying a broad range of CSF SMs and biomarkers of AD, neurodegeneration, and neuroinflammation. Methods: Leveraging two longitudinal AD cohorts with metabolome-wide CSF metabolomics data (n = 502), we analyzed the relationship between the levels of 12 CSF SMs, and AD diagnosis and biomarkers of pathology, neurodegeneration, and neuroinflammation using logistic, linear, and linear mixed effects models. Results: No SMs were significantly associated with AD diagnosis, mild cognitive impairment, or amyloid biomarkers. Phosphorylated tau, neurofilament light, α-synuclein, neurogranin, soluble triggering receptor expressed on myeloid cells 2, and chitinase-3-like-protein 1 were each significantly, positively associated with at least 5 of the SMs. Conclusion: The associations between SMs and biomarkers of neurodegeneration and neuroinflammation, but not biomarkers of amyloid or diagnosis of AD, point to SMs as potential biomarkers for neurodegeneration and neuroinflammation that may not be AD-specific.

Publisher

IOS Press

Subject

Psychiatry and Mental health,Geriatrics and Gerontology,Clinical Psychology,General Medicine,General Neuroscience

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