The circulating proteome and brain health: Mendelian randomisation and cross-sectional analyses

Abstract

AbstractBackgroundDecline in cognitive function is the most feared aspect of ageing. Poorer midlife cognitive function is associated with increased dementia and stroke risk. The mechanisms underlying variation in cognitive function are uncertain.MethodsWe assessed associations between 1160 proteins’ plasma levels and two measures of cognitive function, the digit symbol substitution test (DSST) and the Montreal Cognitive Assessment in 1198 PURE-MIND participants. We assessed key MRI-ascertained structural brain phenotypes as potential mediators of associations between plasma protein levels and cognitive function. Potentially causal effects of protein levels on structural brain phenotypes and neurological outcomes were assessed using Mendelian randomisation (MR) analyses.ResultsWe identified five DSST performance-associated proteins (NCAN, BCAN, CA14, MOG, CDCP1), with NCAN and CDCP1 showing replicated association in an independent cohort, GS (N=1053). MRI-assessed structural brain phenotypes partially mediated (8-19%) associations between NCAN, BCAN, and MOG, and DSST performance. MR analyses suggested higher CA14 levels might cause larger hippocampal volume and increased stroke risk, whilst higher CDCP1 levels might increase stroke and intracranial aneurysm risk.ConclusionsWe identify cognition-associated plasma proteins with potentially causal effects on brain structure and risk for neurological diseases. Our findings highlight candidates for further study and the potential for drug repurposing to reduce risk of stroke and cognitive decline.