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

Abstract

APOEgenotype is the strongest genetic risk factor for late onset Alzheimer's disease, with the ϵ2 and ϵ4 alleles decreasing and increasing risk relative to the ϵ3 allele, respectively. Although evidence has been conflicting, several common infections have been associated with Alzheimer's disease risk, and interactions byAPOEϵ4 carriage have also been reported. Nevertheless, to date, no study has examined relationships betweenAPOEgenotype and measures of multiple common infections among large population-based studies. We investigated associations ofAPOEϵ2 and ϵ4 carriage (i.e. non-carrier vs carrier) with serostatus and antibody titers to 14 common pathogens — encompassing herpesviruses, human polyomaviruses,C.trachomatis,H.pylori, andT.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 ofAPOEϵ2 and ϵ4 dosage (i.e. number of copies of the allele of interest), and ii) relationships ofAPOEgenotype 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 betweenAPOEgenotype and serostatus or antibody titers to any pathogen, with no strong associations observed in any of our analyses following multiple testing correction. Investigations ofAPOEgenotypes with the clinical manifestations of these pathogens, as well as expanding to include other viruses such as SARS-CoV-2, would also be warranted.