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

Rosie M Walker*, Michael Chong, Nicolas Perrot, Marie Pigeyre, Danni A Gadd, Aleks Stolicyn, Liu Shi, Archie Campbell, Xueyi Shen, Heather C Whalley, Alejo Nevado-Holgado, Andrew M McIntosh, Stefan Heitmeier, Sumathy Rangarajan, Martin O'Donnell, Eric E Smith, Salim Yusuf, William N Whiteley, Guillaume Paré*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract / Description of output

Decline 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. Here, we 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 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. Mendelian randomisation analyses suggested higher CA14 levels might cause larger hippocampal volume and increased stroke risk, whilst higher CDCP1 levels might increase intracranial aneurysm risk. Our findings highlight candidates for further study and the potential for drug repurposing to reduce the risk of stroke and cognitive decline.

Original languageEnglish
Pages (from-to)204
JournalTranslational Psychiatry
Issue number1
Publication statusPublished - 18 May 2024

Keywords / Materials (for Non-textual outputs)

  • Humans
  • Mendelian Randomization Analysis
  • Male
  • Female
  • Middle Aged
  • Aged
  • Cross-Sectional Studies
  • Cognitive Dysfunction/blood
  • Brain/diagnostic imaging
  • Proteome
  • Magnetic Resonance Imaging
  • Cognition
  • Stroke/genetics
  • Mental Status and Dementia Tests


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