Systemic inflammation during midlife and cognitive change over 20 years: The ARIC Study

Abstract

Objective: To examine the association between systemic inflammation measured during midlife and 20-year cognitive decline.

Methods: Within the Atherosclerosis Risk in Communities cohort study, inflammatory biomarkers were measured during middle adulthood. We created an inflammation composite score using 4 blood biomarkers measured at visit 1 (fibrinogen, white blood cell count, von Willebrand factor, and factor VIII); we measured C-reactive protein (CRP) at visit 2. Cognition was assessed over 3 visits spanning 20 years using measures of memory, executive function, and language.

Results: A total of 12,336 participants (baseline age 56.8 [5.7], 21% black, 56% women) were included. After adjusting for demographic variables, vascular risk factors, and comorbidities, each standard deviation (SD) increase in midlife inflammation composite score was associated with an additional 20-year decline of -0.035 SD (95% confidence interval: -0.062 to -0.007) on the cognitive composite score. We found a similar association between each SD increase in midlife CRP level and additional 20-year cognitive decline (-0.038 SD, 95% confidence interval: -0.057 to -0.019). Participants with a midlife inflammation composite score in the top quartile had a 7.8% steeper cognitive decline, compared to participants in the lowest quartile; CRP in the top quartile was associated with an 11.6% steeper cognitive decline. In cognitive domain-specific analyses, elevated midlife inflammatory markers were most consistently associated with declines in memory. Results were similar after adjusting for attrition using inverse probability weighting.

Conclusions: Our findings highlight what may be an early pathogenic role for systemic inflammation as a driver of cognitive decline in the decades leading up to older adulthood.

Figure 1. Study flow diagram

Study visits, assessments, and participant numbers are tabulated. ^aWe excluded 42 participants for nonwhite or nonblack race, and 49 black participants living in Minneapolis or Washington County. VWF = von Willebrand factor; WBC = white blood cell count.

Figure 2. Number of elevated inflammatory markers and additional 20-year cognitive decline

Estimates and 95% confidence intervals of additional 20-year cognitive decline from generalized linear models fit using covariate-adjusted generalized estimating equations for composite and domain-specific cognitive decline among participants with 0, 1–2, and 3–4 elevated inflammatory markers. Findings were observed for the composite cognitive score (A), memory (B), executive function (C), and language (D) in domain-specific analyses. Inflammatory marker levels were classified as elevated if they were in the top quartile (≥75th %tile). Models are adjusted for baseline age and age squared, sex, race-center, education, APOE ε4 status, body mass index, total cholesterol, high-density lipoprotein, cigarette and alcohol use status, hypertension, diabetes, coronary heart disease, heart failure, cancer, cholesterol-lowering medication use, and anti-inflammatory medication use, and interactions of demographic variables and medical comorbidity with time spline terms (model 2). DSST = Digit Symbol Substitution Test; DWRT = Delayed Word Recall Test; WFT = Word Fluency Test.