C-reactive protein and cognitive impairment: A bidirectional Mendelian randomization study

While C-reactive protein (CRP) has been solidly linked as a risk factor for cognitive impairment, observational research alone cannot definitively demonstrate a causal relationship. This study therefore sought to determine whether there was an association between CRP and the development of cognitive impairment.

This study employed bidirectional Mendelian randomization (MR) to investigate the genetic association between CRP and cognitive impairment. genome-wide association studies (GWAS) summary statistics for both were sourced from IEU Open GWAS or prior reports. Cognitive GWAS's used were on tests designed to assess cognitive performance, fluid intelligence, prospective memory, and reaction time. The MR analysis applied several methods, including inverse variance-weighted (IVW), MR Egger, weighted median, simple mode, and weighted mode approaches, then use of MR sensitivity analyses to interrogate findings.

Forward MR analysis showed that genetically proxied CRP was associated with prospective memory (P = 0.009), whereas there is little evidence to support an association between CRP and other cognitive tests. Reverse MR analysis indicated a potential association between genetic proxy cognitive performance (P = 0.002) and fluid intelligence score (P = 0.019) with CRP levels. For genetically proxied CRP on prospective memory, the level of pleiotropy (P > 0.05) and no genetic variant heterogeneity (P > 0.05) made bias unlikely, and leave-one-out tests also confirmed robust associations.

The effect of genetically proxied CRP on prospective memory, with little evidence on other cognitive tests. The reverse MR shows some evidence of genetically proxied cognition (cognitive performance and fluid intelligence) on CRP levels.