. 2023 Nov 3;6(1):1117.

doi: 10.1038/s42003-023-05454-1.

Identification of circulating proteins associated with general cognitive function among middle-aged and older adults

Adrienne Tin^#^{1

2}, Alison E Fohner^#^{3

4

5}, Qiong Yang⁶, Jennifer A Brody⁷, Gail Davies⁸, Jie Yao⁹, Dan Liu¹⁰, Ilana Caro¹¹, Joni V Lindbohm^{12

13

14}, Michael R Duggan¹⁵, Osorio Meirelles¹⁶, Sarah E Harris⁸, Valborg Gudmundsdottir^{17

18}, Adele M Taylor⁸, Albert Henry¹⁹, Alexa S Beiser^{6

20}, Ali Shojaie²¹, Annabell Coors¹⁰, Annette L Fitzpatrick^{22

23}, Claudia Langenberg^{24

25

26}, Claudia L Satizabal^{20

27

28}, Colleen M Sitlani⁷, Eleanor Wheeler²⁵, Elliot M Tucker-Drob²⁹, Jan Bressler³⁰, Josef Coresh³¹, Joshua C Bis⁷, Julián Candia³², Lori L Jennings³³, Maik Pietzner^{24

25

26}, Mark Lathrop³⁴, Oscar L Lopez³⁵, Paul Redmond⁸, Robert E Gerszten³⁶, Stephen S Rich³⁷, Susan R Heckbert²², Thomas R Austin^{22

7}, Timothy M Hughes^{38

39}, Toshiko Tanaka³², Valur Emilsson^{17

18}, Ramachandran S Vasan^{20

40

41}, Xiuqing Guo⁹, Yineng Zhu⁶, Christophe Tzourio¹¹, Jerome I Rotter⁹, Keenan A Walker¹⁵, Luigi Ferrucci³², Mika Kivimäki^{42

43}, Monique M B Breteler^{10

44}, Simon R Cox⁸, Stephanie Debette^{11

45}, Thomas H Mosley⁴⁶, Vilmundur G Gudnason¹⁷, Lenore J Launer⁴⁷, Bruce M Psaty^{22

7

48}, Sudha Seshadri^{20

27}, Myriam Fornage^{30

49}

Affiliations

¹ Memory Impairment and Neurodegenerative Dementia (MIND) Center, University of Mississippi Medical Center, Jackson, MS, USA. atin@umc.edu.
² Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA. atin@umc.edu.
³ Department of Epidemiology, University of Washington, Seattle, WA, USA. afohner@uw.edu.
⁴ Institute for Public Health Genetics, University of Washington, Seattle, WA, USA. afohner@uw.edu.
⁵ Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, USA. afohner@uw.edu.
⁶ Department of Biostatistics, Boston University, Boston, MA, USA.
⁷ Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, USA.
⁸ Lothian Birth Cohorts, Department of Psychology, University of Edinburgh, 7 George Square, Edinburgh, EH8 9JZ, UK.
⁹ The Institute for Translational Genomics and Population Sciences, Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA, USA.
¹⁰ Population Health Sciences, German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany.
¹¹ University of Bordeaux, Institut National de la Santé et de la Recherche Médicale (INSERM), Bordeaux Population Health Research Center, UMR 1219, CHU Bordeaux, Bordeaux, France.
¹² Broad Institute of the Massachusetts Institute of Technology and Harvard University, The Klarman Cell Observatory, Cambridge, MA, USA.
¹³ Clinicum, Department of Public Health, University of Helsinki, Helsinki, Finland.
¹⁴ Department of Epidemiology and Public Health, University College London, London, UK.
¹⁵ Laboratory of Behavioral Neuroscience, National Institute on Aging, Baltimore, MD, USA.
¹⁶ National Institute on Aging, National Institutes of Health, Laboratory of Epidemiology and Population Science, Bethesda, MD, USA.
¹⁷ Faculty of Medicine, University of Iceland, Reykjavik, Iceland.
¹⁸ Icelandic Heart Association, Kopavogur, Iceland.
¹⁹ Institute of Cardiovascular Science, University of London, London, UK.
²⁰ Framingham Heart Study, Framingham, MA, USA.
²¹ Department of Biostatistics, University of Washington, Seattle, WA, USA.
²² Department of Epidemiology, University of Washington, Seattle, WA, USA.
²³ Departments of Family Medicine, University of Washington, Seattle, WA, USA.
²⁴ Precision Healthcare Institute, Queen Mary University of London, London, UK.
²⁵ MRC Epidemiology Unit, University of Cambridge, Cambridge, UK.
²⁶ Computational Medicine, Berlin Institute of Health at Charité - Universitätsmedizin Berlin, Berlin, Germany.
²⁷ Department of Population Health Sciences and Glenn Biggs Institute for Alzheimer's & Neurodegenerative Diseases, UT Health San Antonio, San Antonio, TX, USA.
²⁸ Department of Neurology, Boston University School of Medicine, Boston, MA, USA.
²⁹ Department of Psychology, University of Texas, Austin, TX, USA.
³⁰ Human Genetics Center, School of Public Health, University of Texas Health Science Center at Houston, Houston, TX, USA.
³¹ Johns Hopkins University, Baltimore, MD, USA.
³² Translational Gerontology Branch, National Institute on Aging, Baltimore, MD, USA.
³³ Novartis Institutes for Biomedical Research, 22 Windsor Street, Cambridge, MA, USA.
³⁴ McGill Genome Centre, Montreal, QC, Canada.
³⁵ Departments of Neurology and Psychiatry, University of Pittsburgh, Pittsburgh, PA, USA.
³⁶ Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA.
³⁷ Center for Public Health Genomics, Department of Public Health Sciences, University of Virginia, Charlottesville, VA, USA.
³⁸ Department of Internal Medicine, Section of Gerontology and Geriatric Medicine, Wake Forest School of Medicine, Winston-Salem, NC, USA.
³⁹ Department of Epidemiology and Prevention, Wake Forest University School of Medicine, Winston-Salem, NC, USA.
⁴⁰ University of Texas School of Public Health in San Antonio, San Antonio, TX, USA.
⁴¹ University of Texas Health Sciences Center, San Antonio, TX, USA.
⁴² UCL Brain Sciences, University College London, London, UK.
⁴³ Clinicum, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
⁴⁴ Institute for Medical Biometry, Informatics and Epidemiology (IMBIE), Faculty of Medicine, University of Bonn, Bonn, Germany.
⁴⁵ Department of Neurology, Institute for Neurodegenerative Diseases, CHU de Bordeaux, Bordeaux, France.
⁴⁶ Memory Impairment and Neurodegenerative Dementia (MIND) Center, University of Mississippi Medical Center, Jackson, MS, USA.
⁴⁷ Laboratory of Epidemiology and Population Science, National Institute on Aging, National Institutes of Health, Baltimore, MD, USA.
⁴⁸ Department of Health Systems and Population Health, University of Washington, Seattle, WA, USA.
⁴⁹ Institute of Molecular Medicine, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, USA.

^# Contributed equally.

PMID: 37923804
PMCID: PMC10624811
DOI: 10.1038/s42003-023-05454-1

Identification of circulating proteins associated with general cognitive function among middle-aged and older adults

Adrienne Tin et al. Commun Biol. 2023.

. 2023 Nov 3;6(1):1117.

doi: 10.1038/s42003-023-05454-1.

Authors

Affiliations

¹ Memory Impairment and Neurodegenerative Dementia (MIND) Center, University of Mississippi Medical Center, Jackson, MS, USA. atin@umc.edu.
² Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA. atin@umc.edu.
³ Department of Epidemiology, University of Washington, Seattle, WA, USA. afohner@uw.edu.
⁴ Institute for Public Health Genetics, University of Washington, Seattle, WA, USA. afohner@uw.edu.
⁵ Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, USA. afohner@uw.edu.
⁶ Department of Biostatistics, Boston University, Boston, MA, USA.
⁷ Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, USA.
⁸ Lothian Birth Cohorts, Department of Psychology, University of Edinburgh, 7 George Square, Edinburgh, EH8 9JZ, UK.
⁹ The Institute for Translational Genomics and Population Sciences, Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA, USA.
¹⁰ Population Health Sciences, German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany.
¹¹ University of Bordeaux, Institut National de la Santé et de la Recherche Médicale (INSERM), Bordeaux Population Health Research Center, UMR 1219, CHU Bordeaux, Bordeaux, France.
¹² Broad Institute of the Massachusetts Institute of Technology and Harvard University, The Klarman Cell Observatory, Cambridge, MA, USA.
¹³ Clinicum, Department of Public Health, University of Helsinki, Helsinki, Finland.
¹⁴ Department of Epidemiology and Public Health, University College London, London, UK.
¹⁵ Laboratory of Behavioral Neuroscience, National Institute on Aging, Baltimore, MD, USA.
¹⁶ National Institute on Aging, National Institutes of Health, Laboratory of Epidemiology and Population Science, Bethesda, MD, USA.
¹⁷ Faculty of Medicine, University of Iceland, Reykjavik, Iceland.
¹⁸ Icelandic Heart Association, Kopavogur, Iceland.
¹⁹ Institute of Cardiovascular Science, University of London, London, UK.
²⁰ Framingham Heart Study, Framingham, MA, USA.
²¹ Department of Biostatistics, University of Washington, Seattle, WA, USA.
²² Department of Epidemiology, University of Washington, Seattle, WA, USA.
²³ Departments of Family Medicine, University of Washington, Seattle, WA, USA.
²⁴ Precision Healthcare Institute, Queen Mary University of London, London, UK.
²⁵ MRC Epidemiology Unit, University of Cambridge, Cambridge, UK.
²⁶ Computational Medicine, Berlin Institute of Health at Charité - Universitätsmedizin Berlin, Berlin, Germany.
²⁷ Department of Population Health Sciences and Glenn Biggs Institute for Alzheimer's & Neurodegenerative Diseases, UT Health San Antonio, San Antonio, TX, USA.
²⁸ Department of Neurology, Boston University School of Medicine, Boston, MA, USA.
²⁹ Department of Psychology, University of Texas, Austin, TX, USA.
³⁰ Human Genetics Center, School of Public Health, University of Texas Health Science Center at Houston, Houston, TX, USA.
³¹ Johns Hopkins University, Baltimore, MD, USA.
³² Translational Gerontology Branch, National Institute on Aging, Baltimore, MD, USA.
³³ Novartis Institutes for Biomedical Research, 22 Windsor Street, Cambridge, MA, USA.
³⁴ McGill Genome Centre, Montreal, QC, Canada.
³⁵ Departments of Neurology and Psychiatry, University of Pittsburgh, Pittsburgh, PA, USA.
³⁶ Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA.
³⁷ Center for Public Health Genomics, Department of Public Health Sciences, University of Virginia, Charlottesville, VA, USA.
³⁸ Department of Internal Medicine, Section of Gerontology and Geriatric Medicine, Wake Forest School of Medicine, Winston-Salem, NC, USA.
³⁹ Department of Epidemiology and Prevention, Wake Forest University School of Medicine, Winston-Salem, NC, USA.
⁴⁰ University of Texas School of Public Health in San Antonio, San Antonio, TX, USA.
⁴¹ University of Texas Health Sciences Center, San Antonio, TX, USA.
⁴² UCL Brain Sciences, University College London, London, UK.
⁴³ Clinicum, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
⁴⁴ Institute for Medical Biometry, Informatics and Epidemiology (IMBIE), Faculty of Medicine, University of Bonn, Bonn, Germany.
⁴⁵ Department of Neurology, Institute for Neurodegenerative Diseases, CHU de Bordeaux, Bordeaux, France.
⁴⁶ Memory Impairment and Neurodegenerative Dementia (MIND) Center, University of Mississippi Medical Center, Jackson, MS, USA.
⁴⁷ Laboratory of Epidemiology and Population Science, National Institute on Aging, National Institutes of Health, Baltimore, MD, USA.
⁴⁸ Department of Health Systems and Population Health, University of Washington, Seattle, WA, USA.
⁴⁹ Institute of Molecular Medicine, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, USA.

^# Contributed equally.

PMID: 37923804
PMCID: PMC10624811
DOI: 10.1038/s42003-023-05454-1

Abstract

Identifying circulating proteins associated with cognitive function may point to biomarkers and molecular process of cognitive impairment. Few studies have investigated the association between circulating proteins and cognitive function. We identify 246 protein measures quantified by the SomaScan assay as associated with cognitive function (p < 4.9E-5, n up to 7289). Of these, 45 were replicated using SomaScan data, and three were replicated using Olink data at Bonferroni-corrected significance. Enrichment analysis linked the proteins associated with general cognitive function to cell signaling pathways and synapse architecture. Mendelian randomization analysis implicated higher levels of NECTIN2, a protein mediating viral entry into neuronal cells, with higher Alzheimer's disease (AD) risk (p = 2.5E-26). Levels of 14 other protein measures were implicated as consequences of AD susceptibility (p < 2.0E-4). Proteins implicated as causes or consequences of AD susceptibility may provide new insight into the potential relationship between immunity and AD susceptibility as well as potential therapeutic targets.

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Conflict of interest statement

E.W. is now an employee of AstraZeneca. M.K. is supported by the Wellcome Trust (221854/Z/20/Z), the UK Medical Research Council (MR/S011676/1), the US National Institute on Aging (R01AG056477), and the Academy of Finland (329202, 350426). B.P. serves on the Steering Committee of the Yale Open Data Access Project funded by Johnson & Johnson. J.C. serves as a Scientific Advisor to SomaLogic and receives grant support from NIH. Other coauthors have nothing to disclose. L.J. is an employee and stockholder of Novartis. All other authors declare no competing interests.

Figures

**Fig. 1. Flowchart of main analyses.**
General cognitive function was represented by the first unrotated principal component of cognitive scores from 3 or more domains. Abbreviation DSST digit symbol substitution test, ARIC Atherosclerosis Risk in Communities, CHS Cardiovascular Heart Study, FHS Framingham Heart Study, AGES age, gene/environment susceptibility – Reykjavik, BLSA Baltimore Longitudinal Study of Aging, MESA multi-ethnic Study of Atherosclerosis, CARDIA Coronary Artery Risk Development in Young Adults, LBC Lothian Birth Cohort, MR Mendelian randomization.

**Fig. 2. Volcano plots showing the beta coefficients and p-values from the discovery meta-analyses with colors indicating whether a protein was replicated.**
The three discovery analyses were for general cognitive function among aged ≥25 (a) and aged ≥65 (b), and performance on the Digit Symbol Substitution Test (c).

Fig. 3. Gene Ontology (GO) terms that were enriched in the association between circulating proteins and general cognitive function in the discovery meta-analysis among those aged ≥ 25 based on overrepresentation analysis.
The proteins on the horizontal axis (n = 39) were those significant in the discovery meta-analysis and linked to the significant GO terms (Supplementary Data 21). Of these 15 were replicated: ** indicates those replicated at Bonferroni-corrected significance level (n = 7, Supplementary Data 15), and * indicates those replicated only at FDR < 0.05 (n = 8). The size and color of the circles correspond to –log10(p-value) from the discovery meta-analysis (Supplementary Data 9).

See this image and copyright information in PMC

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Identification of circulating proteins associated with general cognitive function among middle-aged and older adults

Affiliations

Identification of circulating proteins associated with general cognitive function among middle-aged and older adults

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

Publication types

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Associated data

Grants and funding

LinkOut - more resources

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Medical