Identification of plasma proteins relating to brain neurodegeneration and vascular pathology in cognitively normal individuals

Liu Shi; Colin R Buchanan; Simon R. Cox; Robert F. Hillary; Riccardo E Marioni; Archie Campbell; Caroline Hayward; Aleks  Stolicyn; Heather C. Whalley; Matthew A. Harris; Jennifer M.J. Waymont; Gordon Waiter; Ellen V. Backhouse; Joanna M. Wardlaw; Douglas Steele; Andrew M.  McIntosh; Simon Lovestone; Noel Buckley; Alejo J. Nevado-Holgado

doi:10.1002/dad2.12240

Identification of plasma proteins relating to brain neurodegeneration and vascular pathology in cognitively normal individuals

Liu Shi^*, Colin R Buchanan, Simon R. Cox, Robert F. Hillary, Riccardo E Marioni, Archie Campbell, Caroline Hayward, Aleks Stolicyn, Heather C. Whalley, Matthew A. Harris, Jennifer M.J. Waymont, Gordon Waiter, Ellen V. Backhouse, Joanna M. Wardlaw, Douglas Steele, Andrew M. McIntosh, Simon Lovestone, Noel Buckley, Alejo J. Nevado-Holgado

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

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Abstract

Introduction
This study aims to first discover plasma proteomic biomarkers relating to neurodegeneration (N) and vascular (V) damage in cognitively normal individuals and second to discover proteins mediating sex-related difference in N and V pathology.

Methods
Five thousand and thirty-two plasma proteins were measured in 1061 cognitively normal individuals (628 females and 433 males), nearly 90% of whom had magnetic resonance imaging measures of hippocampal volume (as N) and white matter hyperintensities (as V).

Results
Differential protein expression analysis and co-expression network analysis revealed different proteins and modules associated with N and V, respectively. Furthermore, causal mediation analysis revealed four proteins mediated sex-related difference in N and one protein mediated such difference in V damage.

Discussion
Once validated, the identified proteins could help to select cognitively normal individuals with N and V pathology for Alzheimer's disease clinical trials and provide targets for further mechanistic studies on brain sex differences, leading to sex-specific therapeutic strategies.

Original language	English
Article number	e12240
Number of pages	12
Journal	Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring
Volume	13
Issue number	1
DOIs	https://doi.org/10.1002/dad2.12240
Publication status	Published - 27 Sept 2021

Bibliographical note

This project was funded by DPUK through MRC (grant no. MR/L023784/2) and the UK Medical Research Council Award to the University of Oxford (grant no. MC_PC_17215). L.S is funded by the Virtual Brain Cloud from European comission (grant no. H2020-SC1-DTH-2018-1). C.R.B is funded by National Institutes of Health (NIH) research grant R01AG054628. S.R.C is funded by National Institutes of Health (NIH) research grant (R01AG054628), Medical Research Council (MR/R024065/1), Age UK and Economic and Social Research Council. R.E.M. was supported by Alzheimer's Research UK major project grant ARUKPG2017B-10. C.H was supported by an MRC Human Genetics Unit programme grant “Quantitative traits in health and disease” (U.MC_UU_00007/10). H.C.W received funding from Wellcome Trust. J.W is funded by TauRx pharmaceuticals Ltd and received Educational grant from Biogen paid to Alzheimer Scotland/Brain Health Scotland. G.W received GRAMPIAN UNIVERSITY HOSPITALS NHS TRUST, Scottish Government—Chief Scientist Office, ROLAND SUTTON ACADEMIC TRUST, Medical Research Scotland, Sutton Academic Trust and ROLAND SUTTON ACADEMIC TRUST. J.M.W received Wellcome Trust Strategic Award, MRC UK Dementia Research Institute and MRC project grants, Fondation Leducq, Stroke Association, British Heart Foundation, Alzheimer Society, and the European Union H2020 PHC-03-15 SVDs@Target grant (666881). D.S received MRC (MR/S010351/1), MRC (MR/W002388/1) and MRC (MR/W002566/1). A.M is supported by the Wellcome Trust (104036/Z/14/Z, 216767/Z/19/Z, 220857/Z/20/Z) and UKRI MRC (MC_PC_17209, MR/S035818/1). This work is part of a project that has received funding from the European Union's Horizon 2020 research and innovation programme under grant agreement No 847776. In addition, A.M has received grant support from The Sackler Trust, outside of the work presented. N.B received grant to institution from GSK as part of GSK/Oxford FxG initiative. A.N.H received John Black Charitable Fund-Rosetrees, H2020 funding from European Comission-Project Virtual Brain Cloud, AI for the Discovery of new therapies in Parkinson's (A2926), Rising Start Initiative—stage 2, Brain-Gut Microbiome (Call: PAR-18-296; Award ID: 1U19AG063744-01), Gut-liver-brain biochemical axis in Alzheimer's disease (5RF1AG057452-01), Virtual Brain Cloud (Call: H2020-SC1-DTH- 2018-1; Grant agreement ID: 826421). Generation Scotland received core support from the Chief Scientist Office of the Scottish Government Health Directorates (CZD/16/6) and the Scottish Funding Council (HR03006) and is currently supported by the Wellcome Trust (216767/Z/19/Z). Genotyping of the GS:SFHS samples was carried out by the Genetics Core Laboratory at the Edinburgh Clinical Research Facility, University of Edinburgh, Scotland and was funded by the Medical Research Council UK and the Wellcome Trust (Wellcome Trust Strategic Award “STratifying Resilience and Depression Longitudinally” [STRADL] Reference 104036/Z/14/Z).

We are grateful to all the families who took part; the general practitioners and the Scottish School of Primary Care for their help in recruiting them; and the whole Generation Scotland team, which includes interviewers, computer and laboratory technicians, clerical workers, research scientists, volunteers, managers, receptionists, health-care assistants, and nurses.

Data Availability Statement

Access to and use of GS and STRADL data must be approved by the GS Access Committee under the terms of consent. Full details of the application process can be found at www.generationscotland.org.

Keywords

meditation
neurodegeneration
plasma proteomics
vascular damage
sex related difference

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Cite this

Shi, L., Buchanan, C. R., Cox, S. R., Hillary, R. F., Marioni, R. E., Campbell, A., Hayward, C., Stolicyn, A., Whalley, H. C., Harris, M. A., Waymont, J. M. J., Waiter, G., Backhouse, E. V., Wardlaw, J. M., Steele, D., McIntosh, A. M., Lovestone, S., Buckley, N., & Nevado-Holgado, A. J. (2021). Identification of plasma proteins relating to brain neurodegeneration and vascular pathology in cognitively normal individuals. Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring, 13(1), Article e12240. https://doi.org/10.1002/dad2.12240

Shi, L, Buchanan, CR, Cox, SR, Hillary, RF, Marioni, RE, Campbell, A, Hayward, C, Stolicyn, A, Whalley, HC, Harris, MA, Waymont, JMJ, Waiter, G, Backhouse, EV, Wardlaw, JM, Steele, D, McIntosh, AM, Lovestone, S, Buckley, N & Nevado-Holgado, AJ 2021, 'Identification of plasma proteins relating to brain neurodegeneration and vascular pathology in cognitively normal individuals', Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring, vol. 13, no. 1, e12240. https://doi.org/10.1002/dad2.12240

@article{2511687c04b547a3acba9433473a3c02,

title = "Identification of plasma proteins relating to brain neurodegeneration and vascular pathology in cognitively normal individuals",

abstract = "IntroductionThis study aims to first discover plasma proteomic biomarkers relating to neurodegeneration (N) and vascular (V) damage in cognitively normal individuals and second to discover proteins mediating sex-related difference in N and V pathology.MethodsFive thousand and thirty-two plasma proteins were measured in 1061 cognitively normal individuals (628 females and 433 males), nearly 90% of whom had magnetic resonance imaging measures of hippocampal volume (as N) and white matter hyperintensities (as V).ResultsDifferential protein expression analysis and co-expression network analysis revealed different proteins and modules associated with N and V, respectively. Furthermore, causal mediation analysis revealed four proteins mediated sex-related difference in N and one protein mediated such difference in V damage.DiscussionOnce validated, the identified proteins could help to select cognitively normal individuals with N and V pathology for Alzheimer's disease clinical trials and provide targets for further mechanistic studies on brain sex differences, leading to sex-specific therapeutic strategies.",

keywords = "meditation, neurodegeneration, plasma proteomics, vascular damage, sex related difference",

author = "Liu Shi and Buchanan, {Colin R} and Cox, {Simon R.} and Hillary, {Robert F.} and Marioni, {Riccardo E} and Archie Campbell and Caroline Hayward and Aleks Stolicyn and Whalley, {Heather C.} and Harris, {Matthew A.} and Waymont, {Jennifer M.J.} and Gordon Waiter and Backhouse, {Ellen V.} and Wardlaw, {Joanna M.} and Douglas Steele and McIntosh, {Andrew M.} and Simon Lovestone and Noel Buckley and Nevado-Holgado, {Alejo J.}",

note = "This project was funded by DPUK through MRC (grant no. MR/L023784/2) and the UK Medical Research Council Award to the University of Oxford (grant no. MC_PC_17215). L.S is funded by the Virtual Brain Cloud from European comission (grant no. H2020-SC1-DTH-2018-1). C.R.B is funded by National Institutes of Health (NIH) research grant R01AG054628. S.R.C is funded by National Institutes of Health (NIH) research grant (R01AG054628), Medical Research Council (MR/R024065/1), Age UK and Economic and Social Research Council. R.E.M. was supported by Alzheimer's Research UK major project grant ARUKPG2017B-10. C.H was supported by an MRC Human Genetics Unit programme grant “Quantitative traits in health and disease” (U.MC_UU_00007/10). H.C.W received funding from Wellcome Trust. J.W is funded by TauRx pharmaceuticals Ltd and received Educational grant from Biogen paid to Alzheimer Scotland/Brain Health Scotland. G.W received GRAMPIAN UNIVERSITY HOSPITALS NHS TRUST, Scottish Government—Chief Scientist Office, ROLAND SUTTON ACADEMIC TRUST, Medical Research Scotland, Sutton Academic Trust and ROLAND SUTTON ACADEMIC TRUST. J.M.W received Wellcome Trust Strategic Award, MRC UK Dementia Research Institute and MRC project grants, Fondation Leducq, Stroke Association, British Heart Foundation, Alzheimer Society, and the European Union H2020 PHC-03-15 SVDs@Target grant (666881). D.S received MRC (MR/S010351/1), MRC (MR/W002388/1) and MRC (MR/W002566/1). A.M is supported by the Wellcome Trust (104036/Z/14/Z, 216767/Z/19/Z, 220857/Z/20/Z) and UKRI MRC (MC_PC_17209, MR/S035818/1). This work is part of a project that has received funding from the European Union's Horizon 2020 research and innovation programme under grant agreement No 847776. In addition, A.M has received grant support from The Sackler Trust, outside of the work presented. N.B received grant to institution from GSK as part of GSK/Oxford FxG initiative. A.N.H received John Black Charitable Fund-Rosetrees, H2020 funding from European Comission-Project Virtual Brain Cloud, AI for the Discovery of new therapies in Parkinson's (A2926), Rising Start Initiative—stage 2, Brain-Gut Microbiome (Call: PAR-18-296; Award ID: 1U19AG063744-01), Gut-liver-brain biochemical axis in Alzheimer's disease (5RF1AG057452-01), Virtual Brain Cloud (Call: H2020-SC1-DTH- 2018-1; Grant agreement ID: 826421). Generation Scotland received core support from the Chief Scientist Office of the Scottish Government Health Directorates (CZD/16/6) and the Scottish Funding Council (HR03006) and is currently supported by the Wellcome Trust (216767/Z/19/Z). Genotyping of the GS:SFHS samples was carried out by the Genetics Core Laboratory at the Edinburgh Clinical Research Facility, University of Edinburgh, Scotland and was funded by the Medical Research Council UK and the Wellcome Trust (Wellcome Trust Strategic Award “STratifying Resilience and Depression Longitudinally” [STRADL] Reference 104036/Z/14/Z). We are grateful to all the families who took part; the general practitioners and the Scottish School of Primary Care for their help in recruiting them; and the whole Generation Scotland team, which includes interviewers, computer and laboratory technicians, clerical workers, research scientists, volunteers, managers, receptionists, health-care assistants, and nurses.",

year = "2021",

month = sep,

day = "27",

doi = "10.1002/dad2.12240",

language = "English",

volume = "13",

journal = "Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring",

issn = "2352-8729",

publisher = "Elsevier",

number = "1",

}

TY - JOUR

T1 - Identification of plasma proteins relating to brain neurodegeneration and vascular pathology in cognitively normal individuals

AU - Shi, Liu

AU - Buchanan, Colin R

AU - Cox, Simon R.

AU - Hillary, Robert F.

AU - Marioni, Riccardo E

AU - Campbell, Archie

AU - Hayward, Caroline

AU - Stolicyn, Aleks

AU - Whalley, Heather C.

AU - Harris, Matthew A.

AU - Waymont, Jennifer M.J.

AU - Waiter, Gordon

AU - Backhouse, Ellen V.

AU - Wardlaw, Joanna M.

AU - Steele, Douglas

AU - McIntosh, Andrew M.

AU - Lovestone, Simon

AU - Buckley, Noel

AU - Nevado-Holgado, Alejo J.

N1 - This project was funded by DPUK through MRC (grant no. MR/L023784/2) and the UK Medical Research Council Award to the University of Oxford (grant no. MC_PC_17215). L.S is funded by the Virtual Brain Cloud from European comission (grant no. H2020-SC1-DTH-2018-1). C.R.B is funded by National Institutes of Health (NIH) research grant R01AG054628. S.R.C is funded by National Institutes of Health (NIH) research grant (R01AG054628), Medical Research Council (MR/R024065/1), Age UK and Economic and Social Research Council. R.E.M. was supported by Alzheimer's Research UK major project grant ARUKPG2017B-10. C.H was supported by an MRC Human Genetics Unit programme grant “Quantitative traits in health and disease” (U.MC_UU_00007/10). H.C.W received funding from Wellcome Trust. J.W is funded by TauRx pharmaceuticals Ltd and received Educational grant from Biogen paid to Alzheimer Scotland/Brain Health Scotland. G.W received GRAMPIAN UNIVERSITY HOSPITALS NHS TRUST, Scottish Government—Chief Scientist Office, ROLAND SUTTON ACADEMIC TRUST, Medical Research Scotland, Sutton Academic Trust and ROLAND SUTTON ACADEMIC TRUST. J.M.W received Wellcome Trust Strategic Award, MRC UK Dementia Research Institute and MRC project grants, Fondation Leducq, Stroke Association, British Heart Foundation, Alzheimer Society, and the European Union H2020 PHC-03-15 SVDs@Target grant (666881). D.S received MRC (MR/S010351/1), MRC (MR/W002388/1) and MRC (MR/W002566/1). A.M is supported by the Wellcome Trust (104036/Z/14/Z, 216767/Z/19/Z, 220857/Z/20/Z) and UKRI MRC (MC_PC_17209, MR/S035818/1). This work is part of a project that has received funding from the European Union's Horizon 2020 research and innovation programme under grant agreement No 847776. In addition, A.M has received grant support from The Sackler Trust, outside of the work presented. N.B received grant to institution from GSK as part of GSK/Oxford FxG initiative. A.N.H received John Black Charitable Fund-Rosetrees, H2020 funding from European Comission-Project Virtual Brain Cloud, AI for the Discovery of new therapies in Parkinson's (A2926), Rising Start Initiative—stage 2, Brain-Gut Microbiome (Call: PAR-18-296; Award ID: 1U19AG063744-01), Gut-liver-brain biochemical axis in Alzheimer's disease (5RF1AG057452-01), Virtual Brain Cloud (Call: H2020-SC1-DTH- 2018-1; Grant agreement ID: 826421). Generation Scotland received core support from the Chief Scientist Office of the Scottish Government Health Directorates (CZD/16/6) and the Scottish Funding Council (HR03006) and is currently supported by the Wellcome Trust (216767/Z/19/Z). Genotyping of the GS:SFHS samples was carried out by the Genetics Core Laboratory at the Edinburgh Clinical Research Facility, University of Edinburgh, Scotland and was funded by the Medical Research Council UK and the Wellcome Trust (Wellcome Trust Strategic Award “STratifying Resilience and Depression Longitudinally” [STRADL] Reference 104036/Z/14/Z). We are grateful to all the families who took part; the general practitioners and the Scottish School of Primary Care for their help in recruiting them; and the whole Generation Scotland team, which includes interviewers, computer and laboratory technicians, clerical workers, research scientists, volunteers, managers, receptionists, health-care assistants, and nurses.

PY - 2021/9/27

Y1 - 2021/9/27

N2 - IntroductionThis study aims to first discover plasma proteomic biomarkers relating to neurodegeneration (N) and vascular (V) damage in cognitively normal individuals and second to discover proteins mediating sex-related difference in N and V pathology.MethodsFive thousand and thirty-two plasma proteins were measured in 1061 cognitively normal individuals (628 females and 433 males), nearly 90% of whom had magnetic resonance imaging measures of hippocampal volume (as N) and white matter hyperintensities (as V).ResultsDifferential protein expression analysis and co-expression network analysis revealed different proteins and modules associated with N and V, respectively. Furthermore, causal mediation analysis revealed four proteins mediated sex-related difference in N and one protein mediated such difference in V damage.DiscussionOnce validated, the identified proteins could help to select cognitively normal individuals with N and V pathology for Alzheimer's disease clinical trials and provide targets for further mechanistic studies on brain sex differences, leading to sex-specific therapeutic strategies.

AB - IntroductionThis study aims to first discover plasma proteomic biomarkers relating to neurodegeneration (N) and vascular (V) damage in cognitively normal individuals and second to discover proteins mediating sex-related difference in N and V pathology.MethodsFive thousand and thirty-two plasma proteins were measured in 1061 cognitively normal individuals (628 females and 433 males), nearly 90% of whom had magnetic resonance imaging measures of hippocampal volume (as N) and white matter hyperintensities (as V).ResultsDifferential protein expression analysis and co-expression network analysis revealed different proteins and modules associated with N and V, respectively. Furthermore, causal mediation analysis revealed four proteins mediated sex-related difference in N and one protein mediated such difference in V damage.DiscussionOnce validated, the identified proteins could help to select cognitively normal individuals with N and V pathology for Alzheimer's disease clinical trials and provide targets for further mechanistic studies on brain sex differences, leading to sex-specific therapeutic strategies.

KW - meditation

KW - neurodegeneration

KW - plasma proteomics

KW - vascular damage

KW - sex related difference

U2 - 10.1002/dad2.12240

DO - 10.1002/dad2.12240

M3 - Article

SN - 2352-8729

VL - 13

JO - Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring

JF - Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring

IS - 1

M1 - e12240

ER -

Identification of plasma proteins relating to brain neurodegeneration and vascular pathology in cognitively normal individuals

Abstract

Bibliographical note

Data Availability Statement

Keywords

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