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. 2021 Sep 27;13(1):e12240.
doi: 10.1002/dad2.12240. eCollection 2021.

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

Liu Shi  1 , Colin R Buchanan  2   3   4 , Simon R Cox  2   3   4 , Robert F Hillary  5 , Riccardo E Marioni  5 , Archie Campbell  5 , Caroline Hayward  5   6 , Aleks Stolicyn  7 , Heather C Whalley  7 , Mathew A Harris  7 , Jennifer Waymont  8 , Gordon Waiter  8 , Ellen Backhouse  9   10 , Joanna M Wardlaw  9   10 , Douglas Steele  11 , Andrew Mcintosh  12   13 , Simon Lovestone  1   14 , Noel J Buckley  1 , Alejo J Nevado-Holgado  1
Affiliations

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

Liu Shi et al. Alzheimers Dement (Amst). .

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.

Keywords: mediation; neurodegeneration; plasma proteomics; sex‐related difference; vascular damage.

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Conflict of interest statement

S.R.C received payment from the Society of Biological Psychiatry (plenary at SOBP2021). R.E.M. is an advisor to the Epigenetic Clock Development Foundation and has received a speaker fee from Illumina. A.C. is member of Edinburgh MVM Research Ethics Committee. J.M.W is involved in European Stroke Organisation Guideline on Covert Small Vessel Disease 2021 and European Stroke Organisation Chair of Conference Planning Group 2021 and 2022. D.S. helped to set up CAPE study. A.M. received speaker fees from Janssen and Illumina. S.L. is an employee of Janssen Medical UK and Co‐founder of Akrivia Health Ltd. He is also named as an inventor on biomarker intellectual property protected by Proteome Sciences and Kings College London unrelated to the current study and within the past 5 years has advised for Optum labs, Merck, SomaLogic, and been the recipient of funding from AstraZeneca and other companies via the IMI funding scheme. N.B. is a member of Mehta Family Centre for Engineering in Medicine, Kanpur, India as well as the editorial board of Stem Cells. A.N.H. is the main PI of a project funded by J&J, and another projects funded by GSK, all unrelated to this study. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
Overview of the study design: 5032 proteins were measured in 1061 cognitively normal individuals who had magnetic resonance imaging (MRI) measurement. Proteome‐wide association study of MRI and protein co‐expression network analysis revealed potential proteins for causal mediation analysis, leading to the finding of proteins mediating sex‐related differences in brain neurodegeneration and vascular damage
FIGURE 2
FIGURE 2
Volcano plot of proteins associated with (A) hippocampal volume and (C) white matter hyperintensities (WMHs). Those proteins with significantly negative correlations (P < .05) are shown in blue, while the proteins with significantly positive correlations (P < .05) are noted in red. Enriched Kyoto Encyclopedia of Genes and Genomes pathways of proteins with significantly negative (blue) and positive (red) associations with (B) hippocampal volume and (D) WMHs. DE, differential expression; FDR, false discovery rate
FIGURE 3
FIGURE 3
Protein modules correlating to hippocampal volume and white matter hyperintensities (WMHs). A, Weighted gene correlation network analysis (WGCNA) of the plasma proteome. This algorithm generated eight modules (M) of co‐expressed proteins. Modules are clustered in the network dendrogram based on their relatedness. B, Analysis of the association of modules with hippocampal volume and WMHs. * and ** denote significant correlations P < 0.05 and P < 0.001 after false discovery rate (FDR) correction, respectively. (C) and (D) Hub proteins noted within the M5 green and M6 red modules, respectively. F, female; M, male; N, neurodegeneration; V, vascular damage
FIGURE 4
FIGURE 4
Protein modules associations with (A‐C) general cognitive score and (D‐E) Alzheimer's disease risk
See this image and copyright information in PMC

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References

    1. Jack CR Jr, Bennett DA, Blennow K, Carrillo MC, Framework NIA‐AAResearch. Toward a biological definition of Alzheimer's disease. Alzheimers Dement. 2018;14:535‐562. - PMC - PubMed
    1. Apostolova LG, Green AE, Babakchanian S, et al. Hippocampal atrophy and ventricular enlargement in normal aging, mild cognitive impairment (MCI), and Alzheimer disease. Alzheimer Dis Assoc Disord. 2012;26(1):17‐27. - PMC - PubMed
    1. Schröder J, Pantel J. Neuroimaging of hippocampal atrophy in early recognition of Alzheimer's disease–a critical appraisal after two decades of research. Psychiatry Res Neuroimaging. 2016;247:71‐78. - PubMed
    1. Seab JP, Jagust WJ, Wong ST, Roos MS, Reed BR, Budinger TF. Quantitative NMR measurements of hippocampal atrophy in Alzheimer's disease. Magn Reson Med. 1988;8:200‐208. - PubMed
    1. Debette S, Schilling S, Duperron MG, Larsson SC, Markus HS. Clinical significance of magnetic resonance imaging markers of vascular brain injury: a systematic review and meta‐analysis. JAMA Neurol. 2019;76:81‐94. - PMC - PubMed