Supplementary Material for: Risk of developing Alzheimer disease in relation to common infections

Introduction
Many studies demonstrate positive associations between infections and Alzheimer disease (AD), suggesting that brain and/or systemic inflammation may impact AD pathogenesis. However, studies of meningitis and AD risk have been limited to animal models or small human cohorts in the United States (U.S.). The objective of this study was to examine the relationship between incident AD and three different types of infections (meningitis, pneumonia, and urinary tract infections [UTIs]) using a population-based sample of U.S. Medicare beneficiaries.
Methods
We created a case-control dataset by frequency matching 4:1 (control:case) by age group, sex, and month/year of the date of AD diagnosis or control selection date. We identified 52,628 newly diagnosed AD cases and 210,512 population-based controls ≥ 67 years of age using comprehensive Medicare claims data from 2016–2018. We classified infections using ICD-9-CM and ICD-10-CM diagnosis codes. We used logistic regression to calculate adjusted odds ratios (ORs) and 95% confidence intervals (CIs) to evaluate the association between AD and each infection separately. We lagged exposures up to 18 months and examined hospitalization or co-morbid sepsis as a proxy for infection severity. Covariates included age, sex, race/ethnicity, and health care utilization.
Results
AD was positively associated with meningitis in individuals hospitalized without superimposed sepsis with a 6-month lag (OR = 2.713, 95% CI 1.277-5.764), and UTIs without superimposed sepsis with an 18-month lag (OR = 1.231, 95% CI 1.101-1.376), and with superimposed sepsis with an 18-month lag (OR = 1.388, 95% CI 1.050-1.835). There was no association between AD and pneumonia in individuals hospitalized with or without superimposed sepsis. When examining infections that occurred in the outpatient setting, the association between AD and UTI remained positive yet attenuated at all time points, however, the association became inverse between AD and pneumonia.
Conclusion
More severe infections, particularly meningitis, may be associated with a higher risk of AD, due to either unmasking of prodromal AD or acceleration of AD pathogenesis in susceptible individuals.