Inflammatory Diseases, Inflammatory Biomarkers, and Alzheimer Disease: An Observational Analysis and Mendelian
Jian Huang1, Bowen Su1, Ville Karhunen1
1From the Department of Epidemiology and Biostatistics (J.H., B.S., V.K., D.G., V.Z., S.P., P.E., K.K.T., M.-r.J., A.D.), School of Public Health, Imperial College London, United Kingdom; Singapore Institute for Clinical Sciences (SICS) (J.H.), Agency for Science, Technology and Research (A*STAR); Center for Life Course Health Research (V.K., S.P., J.A., S.K.-K., M.-r.J.), Faculty of Medicine, Research Unit of Mathematical Sciences (V.K.), University of Oulu, Finland; The Stanley Center for Psychiatric Research (A.A.-O.), Broad Institute of MIT and Harvard, Cambridge, MA; Analytical and Translational Genetics Unit (A.A.-O.), Massachusetts General Hospital, Boston; Institute for Molecular Medicine Finland (A.A.-O.), University of Helsinki; Research Unit of Biomedicine (K.-H.H.), Medical Research Center (MRC), University of Oulu, University Hospital, Finland; Department of Gastroenterology and Metabolism (K.-H.H.), Poznan University of Medical Sciences, Poland; Unit of Primary Care (S.K.-K., M.-r.J.), Oulu University Hospital; Healthcare and Social Services of Selänne (S.K.-K., I.T.), Pyhäjärvi, Finland and City of Oulu; MediCity and Institute of Biomedicine (M.S., S.J.), University of Turku; Department of Clinical Chemistry (T.L.), Fimlab Laboratories, and Finnish Cardiovascular Research Center, Tampere, Faculty of Medicine and Health Technology, Tampere University; Finnish Institute for Health and Welfare (V.S.), Helsinki; Research Centre of Applied and Preventive Cardiovascular Medicine (O.T.R.), University of Turku; Department of Clinical Physiology and Nuclear Medicine (O.T.R.), Turku University Hospital; Centre for Population Health Research (O.T.R.), University of Turku and Turku University Hospital, Finland; Department of Brain Sciences (P.M.M.), Faculty of Medicine, Imperial College London; UK Dementia Research Institute at Imperial College London (P.M.M., P.E.); MRC Centre for Environment and Health (P.E., M.-r.J.), School of Public Health, Imperial College London, United Kingdom; Department of Hygiene and Epidemiology (K.K.T.), University of Ioannina Medical School, Greece; Biocenter Oulu (M.-r.J.), University of Oulu, Finland; and Department of Life Sciences (M.-r.J.), College of Health and Life Sciences, Brunel University London, United Kingdom.
Background And Objectives:
Whether chronic autoimmune inflammatory diseases causally affect the risk of Alzheimer disease (AD) is controversial. We characterized the relationship between inflammatory diseases and risk of AD and explored the role of circulating inflammatory biomarkers in the relationships between inflammatory diseases and AD.
Methods:
We performed observational analyses for chronic autoimmune inflammatory diseases and risk of AD using data from 2,047,513 participants identified in the UK Clinical Practice Research Datalink (CPRD). Using data of a total of more than 1,100,000 individuals from 15 large-scale genome-wide association study data sets, we performed 2-sample Mendelian randomizations (MRs) to investigate the relationships between chronic autoimmune inflammatory diseases, circulating inflammatory biomarker levels, and risk of AD.
Results:
Cox regression models using CPRD data showed that the overall incidence of AD was higher among patients with inflammatory bowel disease (hazard ratio [HR] 1.17; 95% CI 1.15-1.19; p = 2.1 × 10-4), other inflammatory polyarthropathies and systematic connective tissue disorders (HR 1.13; 95% CI 1.12-1.14; p = 8.6 × 10-5), psoriasis (HR 1.13; 95% CI 1.10-1.16; p = 2.6 × 10-4), rheumatoid arthritis (HR 1.08; 95% CI 1.06-1.11; p = 4.0 × 10-4), and multiple sclerosis (HR 1.06; 95% CI 1.04-1.07; p = 2.8 × 10-4) compared with the age (±5 years) and sex-matched comparison groups free from all inflammatory diseases under investigation. Bidirectional MR analysis identified relationships between chronic autoimmune inflammatory diseases and circulating inflammatory biomarkers. Particularly, circulating monokine induced by gamma interferon (MIG) level was suggestively associated with a higher risk of AD (odds ratio from inverse variance weighted [ORIVW] 1.23; 95% CI 1.06-1.42; p IVW = 0.007) and lower risk of Crohn disease (ORIVW 0.73; 95% CI -0.62 to 0.86; p IVW = 1.3 × 10-4). Colocalization supported a common causal single nucleotide polymorphism for MIG and Crohn disease (posterior probability = 0.74), but not AD (posterior probability = 0.03). Using a 2-sample MR approach, genetically predicted risks of inflammatory diseases were not associated with higher AD risk.
Discussion:
Our data suggest that the association between inflammatory diseases and risk of AD is unlikely to be causal and may be a result of confounding. In support, although inflammatory biomarkers showed evidence for causal associations with inflammatory diseases, evidence was weak that they affected both inflammatory disease and AD.
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