Soluble TREM2 and Inflammatory Proteins in Alzheimer’s Disease Cerebrospinal Fluid

Article type: Research Article

Authors: Rauchmann, Boris-Stephan^{a; b} | Sadlon, Angélique^c | Perneczky, Robert^{b; c; d; e; *} | for the Alzheimer’s Disease Neuroimaging Initiative¹

Affiliations: [a] Department of Radiology, University Hospital, LMU Munich, Germany | [b] Department of Psychiatry and Psychotherapy, University Hospital, LMU Munich, Germany | [c] Ageing Epidemiology (AGE) Research Unit, School of Public Health, Imperial College London, UK | [d] German Center for Neurodegenerative Diseases (DZNE) Munich, Germany | [e] Munich Cluster for Systems Neurology (SyNergy), Munich, Germany

Correspondence: [*] Correspondence to: Robert Perneczky, Department of Psychiatry and Psychotherapy, Division of Mental Health of Older Adults, Ludwig-Maximilians-Universität München, Nußbaumstr. 7, 80336 Munich, Germany. Tel.: +49 89 4400 53439; Fax: +49 89 4400 53413; E-mail: [email protected].

Note: [1] Data used in preparation of this article were obtained from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database (http://adni.loni.usc.edu). As such, the investigators within the ADNI contributed to the design and implementation of ADNI and/or provided data but did not participate in analysis or writing of this report. A complete listing of ADNI investigators can be found at: http://adni.loni.usc.edu/wp-content/uploads/how_to_apply/ADNI_Acknowledgement_List.pdf

Abstract: The present study explores the associations of soluble TREM2, an important regulator of microglial activity linked to Alzheimer’s disease (AD), with other known inflammatory proteins in cerebrospinal fluid (CSF). We studied 303 participants, including 89 controls, 135 mild cognitive impairment, and 79 AD dementia patients. Using established CSF biomarkers, subjects were classified according to the National Institute on Aging-Alzheimer’s Association research framework, which groups markers into those of amyloid-β deposition (A), tau pathology (T), and neurodegeneration (N). TNFR1, TNFR2, TGF-β1, TGFβ2, IL-9, TNF-α, ICAM1, and VCAM1 showed significant concentration differences between the ATN groups, with higher concentrations in more advanced disease categories. sTREM2 was positively associated with the pro-inflammatory proteins TNF-α, TNFR1, TNFR2, ICAM1, VCAM1, and IP-10 and negatively with IL-21; also, positive associations with the anti-inflammatory proteins TGFβ1, IL-10, and IL-9 were found. Pathway enrichment analysis highlighted the involvement of sTREM2 in key functional clusters including immunoglobulin and cytokine production and cellular response to lipopolysaccharides, cytokines, and steroid hormones. Our work provides further evidence in support of TREM2 as amarker of neuroinflammatory response in AD.

Keywords: Alzheimer’s disease, biomarker, functional annotation, interactions network, neurodegeneration, neuroinflammation

DOI: 10.3233/JAD-191120

Journal: Journal of Alzheimer's Disease, vol. 73, no. 4, pp. 1615-1626, 2020