Inflammatory Diseases, Inflammatory Biomarkers, and Alzheimer Disease: An Observational Analysis and Mendelian Randomization

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 x 10(-4)), other inflammatory polyarthropathies and systematic connective tissue disorders (HR 1.13; 95% CI 1.12-1.14; p = 8.6 x 10(-5)), psoriasis (HR 1.13; 95% CI 1.10-1.16; p = 2.6 x 10(-4)), rheumatoid arthritis (HR 1.08; 95% CI 1.06-1.11; p = 4.0 x 10(-4)), and multiple sclerosis (HR 1.06; 95% CI 1.04-1.07; p = 2.8 x 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 x 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.