CSF metabolites associated with biomarkers of Alzheimer's disease pathology

Ruocheng Dong; Qiongshi Lu; Hyunseung Kang; Ivonne Suridjan; Gwendlyn Kollmorgen; Norbert Wild; Yuetiva Deming; Carol A Van Hulle; Rozalyn M Anderson; Henrik Zetterberg; Kaj Blennow; Cynthia M Carlsson; Sanjay Asthana; Sterling C Johnson; Corinne D Engelman

doi:10.3389/fnagi.2023.1214932

CSF metabolites associated with biomarkers of Alzheimer's disease pathology

Front Aging Neurosci. 2023 Aug 30:15:1214932. doi: 10.3389/fnagi.2023.1214932. eCollection 2023.

Authors

Ruocheng Dong¹, Qiongshi Lu², Hyunseung Kang², Ivonne Suridjan³, Gwendlyn Kollmorgen⁴, Norbert Wild⁴, Yuetiva Deming^{1

5

6}, Carol A Van Hulle^{5

6}, Rozalyn M Anderson^{5

7}, Henrik Zetterberg^{8

9

10

11

12}, Kaj Blennow^{8

9}, Cynthia M Carlsson^{5

6

7}, Sanjay Asthana^{5

6

7}, Sterling C Johnson^{5

6

7

13}, Corinne D Engelman^{1

6

13}

Affiliations

¹ Department of Population Health Sciences, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, United States.
² Department of Biostatistics and Medical Informatics, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, United States.
³ Roche Diagnostics International Ltd., Rotkreuz, Switzerland.
⁴ Roche Diagnostics GmbH, Penzberg, Germany.
⁵ Department of Medicine, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, United States.
⁶ Wisconsin Alzheimer's Disease Research Center, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, United States.
⁷ Geriatrics Research Education and Clinical Center, Middleton VA Hospital, Madison, WI, United States.
⁸ Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at University of Gothenburg, Mölndal, Sweden.
⁹ Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden.
¹⁰ UK Dementia Research Institute at UCL, London, United Kingdom.
¹¹ Department of Neurodegenerative Disease, UCL Institute of Neurology, London, United Kingdom.
¹² Hong Kong Center for Neurodegenerative Diseases, Hong Kong, Hong Kong SAR, China.
¹³ Wisconsin Alzheimer's Institute, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, United States.

Abstract

Introduction: Metabolomics technology facilitates studying associations between small molecules and disease processes. Correlating metabolites in cerebrospinal fluid (CSF) with Alzheimer's disease (AD) CSF biomarkers may elucidate additional changes that are associated with early AD pathology and enhance our knowledge of the disease.

Methods: The relative abundance of untargeted metabolites was assessed in 161 individuals from the Wisconsin Registry for Alzheimer's Prevention. A metabolome-wide association study (MWAS) was conducted between 269 CSF metabolites and protein biomarkers reflecting brain amyloidosis, tau pathology, neuronal and synaptic degeneration, and astrocyte or microglial activation and neuroinflammation. Linear mixed-effects regression analyses were performed with random intercepts for sample relatedness and repeated measurements and fixed effects for age, sex, and years of education. The metabolome-wide significance was determined by a false discovery rate threshold of 0.05. The significant metabolites were replicated in 154 independent individuals from then Wisconsin Alzheimer's Disease Research Center. Mendelian randomization was performed using genome-wide significant single nucleotide polymorphisms from a CSF metabolites genome-wide association study.

Results: Metabolome-wide association study results showed several significantly associated metabolites for all the biomarkers except Aβ42/40 and IL-6. Genetic variants associated with metabolites and Mendelian randomization analysis provided evidence for a causal association of metabolites for soluble triggering receptor expressed on myeloid cells 2 (sTREM2), amyloid β (Aβ40), α-synuclein, total tau, phosphorylated tau, and neurogranin, for example, palmitoyl sphingomyelin (d18:1/16:0) for sTREM2, and erythritol for Aβ40 and α-synuclein.

Discussion: This study provides evidence that CSF metabolites are associated with AD-related pathology, and many of these associations may be causal.

Keywords: Alzheimer’s disease; CSF NeuroToolKit biomarkers; Mendelian randomization; metabolome-wide association; metabolomics.

Abstract

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