No clear evidence for relationships of Apolipoprotein E genotype with measures of common infections in three UK cohorts

APOE genotype is the strongest genetic risk factor for late onset Alzheimers disease, with the {varepsilon}2 and {varepsilon}4 alleles decreasing and increasing risk relative to the {varepsilon}3 allele, respectively. Although evidence has been conflicting, several common infections have been associated with Alzheimers disease risk, and interactions by APOE {varepsilon}4 carriage have also been reported. Nevertheless, to date, no study has examined relationships between APOE genotype and measures of multiple common infections among large population-based studies. We investigated associations of APOE {varepsilon}2 and {varepsilon}4 carriage (i.e. non-carrier vs carrier) with serostatus and antibody titers to 14 common pathogens - encompassing herpesviruses, human polyomaviruses, C.trachomatis, H.pylori, and T.gondii - in three population-based cohorts (UK Biobank, National Survey of Health and Development, Southall and Brent Revisited). Pathogen serostatus was derived using validated antibody cut-offs for relevant antigens and included as an outcome assessing previous infection. Antibody titers were dichotomised among the seropositive subset for each antigen and included as binary outcomes assessing recent immunological responses. We conducted analyses in each cohort using mixed-models, including age, sex and genetic principal components as fixed-effects, and genetic relatedness as a random-effect. In secondary analyses, we additionally assessed i) relationships of APOE {varepsilon}2 and {varepsilon}4 dosage (i.e. number of copies of the allele of interest), and ii) relationships of APOE genotype with continuous antibody titers (rank-based inverse normal transformed). Findings were meta-analysed across cohorts (n=10,059) using random-effects models and corrected for multiple tests using the false discovery rate. We found no clear evidence of relationships between APOE genotype and serostatus or antibody titers to any pathogen, with no strong associations observed in any of our analyses following multiple testing correction. Investigations of APOE genotypes with the clinical manifestations of these pathogens, as well as expanding to include other viruses such as SARS-CoV-2, would also be warranted.