C-Reactive protein and cognition: Mediation analyses with brain morphology in the UK Biobank

Cognitive impairments and abnormal immune activity are both associated with various clinical disorders. The association between C-Reactive protein (CRP), a marker associated with inflammation, and cognitive perfor-mance remains unclear. Further, mechanisms potentially linking CRP to cognition are not yet established. Brain structure may well mediate this relationship: immune processes play crucial roles in shaping and maintaining brain structure, with brain structure and function driving cognition. The United Kingdom Biobank (UKBB) is a large cohort study with extensive assessments, including high-sensitivity serum CRP levels, brain imaging, and various cognitive tasks. With data from 39,200 UKBB participants, we aimed first to determine the relationship between CRP and cognitive performance, and second, to assess metrics of brain morphology as potential me-diators in this relationship. Participants were aged 40 to 70 at initial assessment and were mostly Caucasian. After accounting for potential covariates (e.g., age, sex, medical diagnoses, use of selective-serotonin reuptake inhibitors), we found CRP levels to have small, negative associations with fluid intelligence (b =-0.03, 95%CI [-0.05,-0.02], t(14381) =-3.62, pcor = .004), and numeric memory (b =-0.03, 95%CI[-0.05,-0.01], t(14366) =-3.31, pcor = .007). We found no evidence of brain morphology mediating these relationships (all |ab| < 0.001, allpcor > .55). Our findings from this large sample suggest that serum-assessed CRP is of marginal importance for cognitive performance in mid-to-late aged Caucasians; the small effect sizes of statistically significant associa-tions provide context to previous inconsistent results. The seeming lack of involvement of brain morphology suggests that other brain metrics (e.g., connectivity, functional activation) may be more pertinent to this rela-tionship. Future work should also consider CRP levels measured in the central nervous system and/or other cytokines that may better predict cognitive performance in this population.