Science

Keenan A. Walker, PhD, Rebecca F. Gottesman, MD, PhD, Aozhou Wu, MHS, David S. Knopman, MD, Alden L. Gross, PhD, MHS, Thomas H. Mosley, Jr., PhD, Elizabeth Selvin, PhD, MPH, and
B. Gwen Windham, MD, MHS

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 stan- dard 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.