The association of serum immunoglobulins with cognition and dementia: The Rotterdam Study

Abstract

AbstractBackgroundChronic neuro‐inflammation has emerged in recent years as important pathological process underlying dementia, including Alzheimer’s disease. Most studies so far have investigated the innate immune system, but the role of the adaptive immune system remains largely unknown. We investigated the association of serum immunoglobulins (IgA, IgG, IgM) as markers of the adaptive immune system with cognitive function and risk of dementia.MethodThis study was embedded in the Rotterdam Study, an ongoing prospective population based cohort study, and included participants with baseline measurements (between 1997 and 2009) of serum immunoglobulins and informed consent for follow‐up. We performed Cox proportional hazard regression analyses to obtain hazard ratios (HRs) and 95% confidence intervals (CIs) for the association between serum immunoglobulins and risk of dementia until 2016 (longitudinal). We performed linear regression analyses to quantify the cross‐sectional association between serum immunoglobulins and cognition summarized into global cognition as well as separate cognitive test scores. Effect estimates are adjusted for age, sex, lifestyle and cardiovascular factors.ResultWe have included 8,768 participants with a mean age of 64 years and of whom 57% are female. Due to non‐proportional hazards, the follow‐up time was divided into two strata (≤10 and >10 years). We found that IgM was associated with a lower risk of dementia after ten years in women (HR: 0.71; 95% CI: 0.58‐0.86). When restricting analyses to participants with immunoglobulin levels within the reference range and excluding users of immunomodulating medication, we found that IgM was associated with a lower risk of dementia after 10 years in the entire population (HR: 0.78; 95% CI: 0.62‐0.97). We furthermore found that higher IgG levels were associated with lower scores of global cognition, Stroop I, and Stroop II (betas ranging from ‐0.01 to ‐0.02; p‐value <0.002 for all).ConclusionHigher IgM levels are associated with a decreased risk of dementia in women and in all participants with reference range immunoglobulin levels. Higher IgG levels are associated with worse cognitive test outcomes. Our results suggest a protective effect of the adaptive immune system on dementia onset, but possibly a reversed effect on cognitive function.