Lipopolysaccharide-Binding Protein, Soluble CD14, and the Long-Term Risk of Alzheimer’s Disease: A Nested Case-Control Pilot Study of Older Community Dwellers from the Three-City Cohort

Article type: Research Article

Authors: André, Perrine^{a; *} | Samieri, Cécilia^a | Buisson, Charline^b | Dartigues, Jean-François^a | Helmer, Catherine^c | Laugerette, Fabienne^b | Féart, Catherine^a

Affiliations: [a] Université de Bordeaux, Inserm, Bordeaux Population Health Research Center, team Lifelong Exposure Health and Aging, U1219, Bordeaux, France | [b] Univ-Lyon, CarMeN laboratory, INRA U1397, Inserm U1060, Université Claude Bernard Lyon 1, INSA Lyon, Charles Mérieux Medical School, Oullins, France | [c] INSERM, Clinical Investigation Center – Clinical Epidemiology, Bordeaux, France

Correspondence: [*] Correspondence to: Perrine André, MPH, Team “Lifelong Exposures, Health and Aging”, INSERM U1219 – Bordeaux Population Health Research Center, Bordeaux University, ISPED 146 rue Léo-Saignat, Bordeaux Cedex–France. Tel.: +33 05 57 57 12 99; E-mail: [email protected].

Abstract: Background:Identifying the mechanisms involved in the pathogenesis of Alzheimer’s disease (AD) remains crucially important. Chronic age-related low-grade inflammation is considered to be one such mechanism, although its causes are unclear. Lipopolysaccharide (LPS)-type endotoxins, a major component of the outer membrane of Gram-negative bacteria, are known as potent pro-inflammatory molecules. Therefore, we hypothesized that greater exposure to circulating LPS, potentially mediated by the inflammatory pathway, would be a key step of the onset of AD. Objective:The aim of this study was to investigate the link between plasma endotoxin-exposure, inflammation, and AD. Methods:Applying a nested case-control design, we evaluated the associations among baseline plasma endotoxin-exposure (assessed by measuring LPS-binding protein (LBP) and soluble cluster of differentiation-14 (sCD14) levels), inflammation (assessed by measuring interleukin-6 (IL6) levels), and the odds of developing AD over 12 years. Selected from a population-based cohort, 212 incident cases of AD were matched with 424 controls without dementia with regard to age, gender, and education level. Results:After adjusting for a large set of confounders, including the use of anti-inflammatory drugs, only higher LBP levels were significantly associated with a 30% higher odds of developing AD over 12 years (OR 1.30, 95% CIs [1.07–1.59]), regardless of IL6 levels. Conclusion:This large case-control study provides preliminary results concerning plasma endotoxin-exposure among the elderly and suggests that higher LBP levels, an acute-phase reactant involved in the pro-inflammatory response to LPS, are associated with higher odds of developing AD.

Keywords: Alzheimer’s disease, dementia, endotoxins, inflammation, interleukin-6, lipopolysaccharide, lipopolysaccharide-binding protein, soluble cluster of differentiation-14

DOI: 10.3233/JAD-190295

Journal: Journal of Alzheimer's Disease, vol. 71, no. 3, pp. 751-761, 2019