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.

Details

Title
The circulating proteome and brain health: Mendelian randomisation and cross-sectional analyses
Author
Walker, Rosie M. 1   VIAFID ORCID Logo  ; Chong, Michael 2 ; Perrot, Nicolas 3   VIAFID ORCID Logo  ; Pigeyre, Marie 4   VIAFID ORCID Logo  ; Gadd, Danni A. 5   VIAFID ORCID Logo  ; Stolicyn, Aleks 6   VIAFID ORCID Logo  ; Shi, Liu 7 ; Campbell, Archie 8   VIAFID ORCID Logo  ; Shen, Xueyi 6   VIAFID ORCID Logo  ; Whalley, Heather C. 9   VIAFID ORCID Logo  ; Nevado-Holgado, Alejo 10   VIAFID ORCID Logo  ; McIntosh, Andrew M. 6   VIAFID ORCID Logo  ; Heitmeier, Stefan 11   VIAFID ORCID Logo  ; Rangarajan, Sumathy 3 ; O’Donnell, Martin 12 ; Smith, Eric E. 13   VIAFID ORCID Logo  ; Yusuf, Salim 4 ; Whiteley, William N. 14   VIAFID ORCID Logo  ; Paré, Guillaume 15   VIAFID ORCID Logo 

1  Hamilton Health Sciences and McMaster University, Population Health Research Institute, Hamilton, Canada (GRID:grid.413615.4) (ISNI:0000 0004 0408 1354); University of Exeter, School of Psychology, Exeter, UK (GRID:grid.8391.3) (ISNI:0000 0004 1936 8024); The University of Edinburgh, Centre for Clinical Brain Sciences, Edinburgh, UK (GRID:grid.4305.2) (ISNI:0000 0004 1936 7988) 
2  Hamilton Health Sciences and McMaster University, Population Health Research Institute, Hamilton, Canada (GRID:grid.413615.4) (ISNI:0000 0004 0408 1354); McMaster University, Department of Pathology and Molecular Medicine, Faculty of Health Sciences, Hamilton, Canada (GRID:grid.25073.33) (ISNI:0000 0004 1936 8227) 
3  Hamilton Health Sciences and McMaster University, Population Health Research Institute, Hamilton, Canada (GRID:grid.413615.4) (ISNI:0000 0004 0408 1354) 
4  Hamilton Health Sciences and McMaster University, Population Health Research Institute, Hamilton, Canada (GRID:grid.413615.4) (ISNI:0000 0004 0408 1354); McMaster University, Department of Medicine, Michael G DeGroote School of Medicine, Faculty of Health Sciences, Hamilton, Canada (GRID:grid.25073.33) (ISNI:0000 0004 1936 8227) 
5  University of Edinburgh, Centre for Genomic and Experimental Medicine, Institute of Genetics and Cancer, Edinburgh, UK (GRID:grid.4305.2) (ISNI:0000 0004 1936 7988) 
6  The University of Edinburgh, Centre for Clinical Brain Sciences, Edinburgh, UK (GRID:grid.4305.2) (ISNI:0000 0004 1936 7988) 
7  University of Oxford, Department of Psychiatry, Oxford, UK (GRID:grid.4991.5) (ISNI:0000 0004 1936 8948); Nxera Pharma UK Limited, Cambridge, UK (GRID:grid.4991.5) 
8  University of Edinburgh, Generation Scotland, Centre for Genomic and Experimental Medicine, Institute of Genetics and Cancer, Edinburgh, UK (GRID:grid.4305.2) (ISNI:0000 0004 1936 7988) 
9  The University of Edinburgh, Centre for Clinical Brain Sciences, Edinburgh, UK (GRID:grid.4305.2) (ISNI:0000 0004 1936 7988); University of Edinburgh, Generation Scotland, Centre for Genomic and Experimental Medicine, Institute of Genetics and Cancer, Edinburgh, UK (GRID:grid.4305.2) (ISNI:0000 0004 1936 7988) 
10  Nxera Pharma UK Limited, Cambridge, UK (GRID:grid.4305.2) 
11  R&D, Bayer AG, Pharmaceuticals, Wuppertal, Germany (GRID:grid.420044.6) (ISNI:0000 0004 0374 4101) 
12  Hamilton Health Sciences and McMaster University, Population Health Research Institute, Hamilton, Canada (GRID:grid.413615.4) (ISNI:0000 0004 0408 1354); University of Galway, Health Research Board Clinical Research Facility, Galway, Ireland (GRID:grid.6142.1) (ISNI:0000 0004 0488 0789) 
13  Hamilton Health Sciences and McMaster University, Population Health Research Institute, Hamilton, Canada (GRID:grid.413615.4) (ISNI:0000 0004 0408 1354); Cumming School of Medicine, Department of Clinical Neurosciences and Hotchkiss Brain Institute, Calgary, Canada (GRID:grid.22072.35) (ISNI:0000 0004 1936 7697); University of Calgary, Calgary, Canada (GRID:grid.22072.35) (ISNI:0000 0004 1936 7697); University of Calgary, Department of Clinical Neurosciences, Calgary, Canada (GRID:grid.22072.35) (ISNI:0000 0004 1936 7697) 
14  Hamilton Health Sciences and McMaster University, Population Health Research Institute, Hamilton, Canada (GRID:grid.413615.4) (ISNI:0000 0004 0408 1354); The University of Edinburgh, Centre for Clinical Brain Sciences, Edinburgh, UK (GRID:grid.4305.2) (ISNI:0000 0004 1936 7988); University of Oxford, MRC Centre for Population Health, Oxford, UK (GRID:grid.4991.5) (ISNI:0000 0004 1936 8948) 
15  Hamilton Health Sciences and McMaster University, Population Health Research Institute, Hamilton, Canada (GRID:grid.413615.4) (ISNI:0000 0004 0408 1354); McMaster University, Department of Pathology and Molecular Medicine, Faculty of Health Sciences, Hamilton, Canada (GRID:grid.25073.33) (ISNI:0000 0004 1936 8227); Hamilton Health Sciences and McMaster University, Thrombosis and Atherosclerosis Research Institute, Hamilton, Canada (GRID:grid.413615.4) (ISNI:0000 0004 0408 1354) 
Pages
204
Publication year
2024
Publication date
2024
Publisher
Nature Publishing Group
e-ISSN
21583188
Source type
Scholarly Journal
Language of publication
English
DOI
https://doi.org/10.1038/s41398-024-02915-x
ProQuest document ID
3056252332
Copyright
© The Author(s) 2024. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.