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

Abstract (English)

BACKGROUND AND OBJECTIVES: Associations of common infections with Alzheimer disease (AD) risk have been reported. A hypothesized mechanism for these is cerebral &#x3b2;-amyloid (A&#x3b2;) 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 A&#x3b2; 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 <i>APOE</i> &#x3b5;4 carriage and education, respectively. We also tested for interactions in associations by <i>APOE</i> &#x3b5;4 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 A&#x3b2;-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 A&#x3b2;-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 A&#x3b2;-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 <i>Toxoplasma gondii</i> (OR 1.69; 95% CI 0.94-3.05). There were also potential interactions in p-tau217 associations by <i>APOE</i> &#x3b5;4 carriage (for <i>Helicobacter pylori</i> and CMV) and educational attainment (for <i>H pylori</i>). DISCUSSION: These findings do not imply associations between exposures to many common infections and AD neuropathologies. The possibility of pathogen interactions with <i>APOE</i> &#x3b5;4 carriage and education in relation to AD neuropathology warrants further study.