Associations of Antibodies Against Several Infections With Alzheimer Disease Neuropathology: A Prospective Cohort Study Analysis

BACKGROUND AND OBJECTIVES: Associations of common infections with Alzheimer disease (AD) risk have been reported. A hypothesized mechanism for these is cerebral β-amyloid (Aβ) aggregation as a defense to infection. We studied whether serologic measures of several infections in the UK population are associated with measures of AD neuropathology. METHODS: This prospective association study used data from the 1946 British birth cohort. Circulating 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 immunologic activity against pathogens). Associations of these were tested with plasma phosphorylated tau at threonine 217 (p-tau217) (primary outcome) and Aβ status (secondary outcome), measured with PET scans, at ages 69-71 years. Modelling used multivariable quantile and logistic regression. Model 1 adjusted for sex and ages at serology and outcome assessment, and models 2 and 3 additionally adjusted for APOE ε4 carriage and education, respectively. We also tested for interactions in associations by APOE ε4 carriage, education, and sex, and for interactions between herpes simplex virus 1 exposure with cytomegalovirus (CMV) and varicella zoster virus (VZV) exposure. RESULTS: A total of 1,356 and 424 individuals had complete data for p-tau217 and Aβ-PET analyses, respectively. Mean age at p-tau217 was 69.9 years (SD 0.7), and 51.3% of participants were female. Median p-tau217 was 0.30 pg/mL (interquartile range 0.21-0.44). 28.3% had Aβ-positive scans. No notable associations were observed for serology measures with either outcome in main models, except for an unexpected association of herpes simplex virus 2 seropositivity with lower p-tau217 at the 75th quantile (-0.07 pg/mL in seropositive individuals; 95% CI -0.10 to -0.03). Odds of Aβ-PET positivity may have been higher for individuals seropositive for Epstein-Barr virus (odds ratio [OR] 2.84; 95% CI 0.95-8.52) and Toxoplasma gondii (OR 1.69; 95% CI 0.94-3.05). There were also potential interactions in p-tau217 associations by APOE ε4 carriage (for Helicobacter pylori and CMV) and educational attainment (for H pylori). DISCUSSION: These findings do not imply associations between exposures to many common infections and AD neuropathologies. The possibility of pathogen interactions with APOE ε4 carriage and education in relation to AD neuropathology warrants further study.