Associations of antibodies against several infections with Alzheimer disease neuropathology: a prospective cohort study analysis

Background and ObjectivesAssociations of common infections with Alzheimer disease (AD) risk have been reported. A hypothesized mechanism to explain these is cerebral amyloid-beta (A{beta}) aggregation as a defence in response to infection, with subsequent tau accumulation. However, few studies have assessed associations of infections with tau and A{beta} pathology. We investigated associations of serological measures of several common infections with plasma p-tau217 and A{beta} status measured by neuroimaging in the 1946 British birth cohort. MethodsCirculating antibodies against 14 pathogens, measured at age 60-64 years, were modelled as pathogen serostatus (indicating lifetime exposure to an agent), pathogen burden indices (measuring cumulative exposure to 2+ pathogens), and seroreactivity tertiles (indicating recent immunological activity against pathogens). Associations of these were tested with plasma p-tau217 (primary outcome) and A{beta} status measured by positron emission tomography imaging (A{beta}-PET; secondary outcome), measured approximately 7 years after serology measurements. Modelling used multivariable quantile and logistic regression, respectively. Model 1 adjusted for sex and ages at serology and outcome assessment, models 2 and 3 additionally adjusted for APOE {varepsilon}4 carriage and education, respectively. We also tested for interactions in associations with APOE {varepsilon}4 carriage and education, and for interactions between herpes simplex virus 1 (HSV1) exposure with both cytomegalovirus (CMV) and varicella zoster virus (VZV) exposure. Results1356 and 424 individuals had complete data for p-tau217 and A{beta}-PET analyses, respectively. Mean age at p-tau217 was 69.9 years (SD 0.7) and 51.3% of participants were female. No notable associations were observed for either outcome in main models, with the exception being an unexpected relationship between seropositivity for herpes simplex virus 2 and lower p-tau217 at the 75th quantile. There was also some evidence for potential interactions in p-tau217 associations by APOE {varepsilon}4 carriage (for Helicobacter pylori and CMV) and by educational attainment (for Helicobacter pylori serostatus). DiscussionThese findings are not supportive of associations between exposures to many common infections and aggregation of core AD neuropathology measures. The possibility that some pathogens might interact with APOE {varepsilon}4 carriage and education in relation to AD neuropathology warrants further study.