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

Article type: Research Article

Authors: Morrow, Autumn^a | Panyard, Daniel J.^{b; *} | Deming, Yuetiva K.^{a; c; d} | Jonaitis, Erin^{c; e} | Dong, Ruocheng^a | Vasiljevic, Eva^{a; f} | Betthauser, Tobey J.^{c; d} | Kollmorgen, Gwendlyn^g | Suridjan, Ivonne^h | Bayfield, Anna^g | Van Hulle, Carol A.^{c; d} | Zetterberg, Henrik^{i; j; k; l; m} | Blennow, Kaj^{i; j} | Carlsson, Cynthia M.^{c; d; n} | Asthana, Sanjay^{c; d; n} | Johnson, Sterling C.^{c; d; n} | Engelman, Corinne D.^a

Affiliations: [a] Department of Population Health Sciences, University of Wisconsin-Madison, Madison, WI, USA | [b] Department of Genetics, School of Medicine, Stanford University, Stanford, CA, USA | [c] Wisconsin Alzheimer’s Disease Research Center, University of Wisconsin-Madison, Madison, WI, USA | [d] Department of Medicine, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, USA | [e] Wisconsin Alzheimer’s Institute, UW School of Medicine and Public Health, Madison, WI, USA | [f] Center for Demography of Health and Aging, University of Wisconsin-Madison, Madison, WI, USA | [g] Roche Diagnostics GmbH, Penzberg, Germany | [h] Roche Diagnostics International Ltd, Rotkreuz, Switzerland | [i] Institute of Neuroscience and Physiology, The Sahlgrenska Academy at University of Gothenburg, Mölndal, Sweden | [j] Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden | [k] United Kingdom Dementia Research Institute at UCL, London, United Kingdom | [l] Department of Neurodegenerative Disease, UCL Institute of Neurology, London, United Kingdom | [m] Hong Kong Center for Neurodegenerative Diseases, Hong Kong, China | [n] William S. Middleton Memorial Veterans Hospital, 2500 Overlook Terrace, Madison, WI, USA

Correspondence: [*] Correspondence to: Daniel J. Panyard, 3165 Porter Drive, Palo Alto, CA 94304, USA. E-mail:dpanyard@stanford.edu.

Note: [1] This article received a correction notice (Erratum) with the reference: 10.3233/JAD-229019, available at http://doi.org/10.3233/JAD-229019.

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.

Keywords: Alzheimer’s disease, biomarkers, cerebrospinal fluid, metabolomics, neurodegeneration, neuroinflammation, sphingolipid, sphingomyelin

DOI: 10.3233/JAD-220349

Journal: Journal of Alzheimer's Disease, vol. 90, no. 2, pp. 667-680, 2022