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

doi:10.1038/s41398-024-02915-x

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

Transl Psychiatry. 2024 May 18;14(1):204. doi: 10.1038/s41398-024-02915-x.

Authors

Rosie M Walker^#^{1

2

3}, Michael Chong^#^{4

5}, Nicolas Perrot⁴, Marie Pigeyre^{4

6}, Danni A Gadd⁷, Aleks Stolicyn⁸, Liu Shi^{9

10}, Archie Campbell¹¹, Xueyi Shen⁸, Heather C Whalley^{8

11}, Alejo Nevado-Holgado¹⁰, Andrew M McIntosh⁸, Stefan Heitmeier¹², Sumathy Rangarajan⁴, Martin O'Donnell^{4

13}, Eric E Smith^{4

14

15

16}, Salim Yusuf^{4

6}, William N Whiteley^{4

8

17}, Guillaume Paré^{18

19

20}

Affiliations

¹ Population Health Research Institute, Hamilton Health Sciences and McMaster University, Hamilton, ON, Canada. [email protected].
² School of Psychology, University of Exeter, Perry Road, Exeter, UK. [email protected].
³ Centre for Clinical Brain Sciences, The University of Edinburgh, Edinburgh, UK. [email protected].
⁴ Population Health Research Institute, Hamilton Health Sciences and McMaster University, Hamilton, ON, Canada.
⁵ Department of Pathology and Molecular Medicine, Faculty of Health Sciences, McMaster University, Hamilton, ON, Canada.
⁶ Department of Medicine, Michael G DeGroote School of Medicine, Faculty of Health Sciences, McMaster University, Hamilton, ON, Canada.
⁷ Centre for Genomic and Experimental Medicine, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK.
⁸ Centre for Clinical Brain Sciences, The University of Edinburgh, Edinburgh, UK.
⁹ Department of Psychiatry, University of Oxford, Oxford, UK.
¹⁰ Nxera Pharma UK Limited, Cambridge, UK.
¹¹ Generation Scotland, Centre for Genomic and Experimental Medicine, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, EH4 2XU, UK.
¹² Bayer AG, Pharmaceuticals, R&D, 42113, Wuppertal, Germany.
¹³ Health Research Board Clinical Research Facility, University of Galway, Galway, Ireland.
¹⁴ Department of Clinical Neurosciences and Hotchkiss Brain Institute, Cumming School of Medicine, Calgary, AB, Canada.
¹⁵ University of Calgary, Calgary, AB, Canada.
¹⁶ Department of Clinical Neurosciences, University of Calgary, Calgary, AB, Canada.
¹⁷ MRC Centre for Population Health, University of Oxford, Oxford, UK.
¹⁸ Population Health Research Institute, Hamilton Health Sciences and McMaster University, Hamilton, ON, Canada. [email protected].
¹⁹ Department of Pathology and Molecular Medicine, Faculty of Health Sciences, McMaster University, Hamilton, ON, Canada. [email protected].
²⁰ Thrombosis and Atherosclerosis Research Institute, Hamilton Health Sciences and McMaster University, Hamilton, ON, Canada. [email protected].

^# Contributed equally.

Abstract

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.

MeSH terms

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

Abstract

MeSH terms

Grants and funding