Plasma proteins, cognitive decline, and 20-year risk of dementia in the Whitehall II and Atherosclerosis Risk in Communities studies

Joni V Lindbohm^{1

2}, Nina Mars³, Keenan A Walker⁴, Archana Singh-Manoux^{1

5}, Gill Livingston^{6

7}, Eric J Brunner¹, Pyry N Sipilä², Kalle Saksela⁸, Jane E Ferrie^{1

9}, Ruth C Lovering¹⁰, Stephen A Williams¹¹, Aroon D Hingorani^{12

13

14}, Rebecca F Gottesman¹⁵, Henrik Zetterberg^{16

17

18}, Mika Kivimäki^{1

2}

Affiliations

¹ Department of Epidemiology and Public Health, University College London, London, UK.
² Department of Public Health Clinicum, University of Helsinki, Helsinki, Finland.
³ Institute for Molecular Medicine Finland (FIMM) HiLIFE, University of Helsinki, Helsinki, Finland.
⁴ Laboratory of Behavioral Neuroscience, Intramural Research Program, National Institute on Aging, Baltimore, Maryland, USA.
⁵ Epidemiology of Ageing and Neurodegenerative diseases, Université de Paris, Paris, France.
⁶ Division of Psychiatry, University College London, London, UK.
⁷ Camden and Islington Foundation Trust, London, UK.
⁸ Department of Virology, University of Helsinki and HUSLAB, Helsinki University Hospital, Helsinki, Finland.
⁹ Bristol Medical School (PHS), University of Bristol, Bristol, UK.
¹⁰ Functional Gene Annotation, Institute of Cardiovascular Science, University College London, London, UK.
¹¹ SomaLogic, Inc., Boulder, Colorado, USA.
¹² Institute of Cardiovascular Science, University College London, London, UK.
¹³ British Heart Foundation Research Accelerator, University College London, London, UK.
¹⁴ Health Data Research, London, UK.
¹⁵ Department of Neurology, The Johns Hopkins University, Baltimore, Maryland, USA.
¹⁶ Department of Neurodegenerative Disease and UK Dementia Research Institute, University College London, London, UK.
¹⁷ Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
¹⁸ Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden.

PMID: 34338426
PMCID: PMC9292245
DOI: 10.1002/alz.12419

Plasma proteins, cognitive decline, and 20-year risk of dementia in the Whitehall II and Atherosclerosis Risk in Communities studies

Joni V Lindbohm et al. Alzheimers Dement. 2022 Apr.

. 2022 Apr;18(4):612-624.

doi: 10.1002/alz.12419. Epub 2021 Aug 2.

Authors

Affiliations

¹ Department of Epidemiology and Public Health, University College London, London, UK.
² Department of Public Health Clinicum, University of Helsinki, Helsinki, Finland.
³ Institute for Molecular Medicine Finland (FIMM) HiLIFE, University of Helsinki, Helsinki, Finland.
⁴ Laboratory of Behavioral Neuroscience, Intramural Research Program, National Institute on Aging, Baltimore, Maryland, USA.
⁵ Epidemiology of Ageing and Neurodegenerative diseases, Université de Paris, Paris, France.
⁶ Division of Psychiatry, University College London, London, UK.
⁷ Camden and Islington Foundation Trust, London, UK.
⁸ Department of Virology, University of Helsinki and HUSLAB, Helsinki University Hospital, Helsinki, Finland.
⁹ Bristol Medical School (PHS), University of Bristol, Bristol, UK.
¹⁰ Functional Gene Annotation, Institute of Cardiovascular Science, University College London, London, UK.
¹¹ SomaLogic, Inc., Boulder, Colorado, USA.
¹² Institute of Cardiovascular Science, University College London, London, UK.
¹³ British Heart Foundation Research Accelerator, University College London, London, UK.
¹⁴ Health Data Research, London, UK.
¹⁵ Department of Neurology, The Johns Hopkins University, Baltimore, Maryland, USA.
¹⁶ Department of Neurodegenerative Disease and UK Dementia Research Institute, University College London, London, UK.
¹⁷ Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
¹⁸ Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden.

PMID: 34338426
PMCID: PMC9292245
DOI: 10.1002/alz.12419

Abstract

Introduction: Plasma proteins affect biological processes and are common drug targets but their role in the development of Alzheimer's disease and related dementias remains unclear. We examined associations between 4953 plasma proteins and cognitive decline and risk of dementia in two cohort studies with 20-year follow-ups.

Methods: In the Whitehall II prospective cohort study proteins were measured using SOMAscan technology. Cognitive performance was tested five times over 20 years. Linkage to electronic health records identified incident dementia. The results were replicated in the Atherosclerosis Risk in Communities (ARIC) study.

Results: Fifteen non-amyloid/non-tau-related proteins were associated with cognitive decline and dementia, were consistently identified in both cohorts, and were not explained by known dementia risk factors. Levels of six of the proteins are modifiable by currently approved medications for other conditions.

Discussion: This study identified several plasma proteins in dementia-free people that are associated with long-term risk of cognitive decline and dementia.

Keywords: cognitive decline; cohort study; dementia; longitudinal study; proteomics.

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Conflict of interest statement

In this academic–industry partnership project, academic collaborators generated the hypothesis and study design and SomaLogic, Inc. provided expertise in plasma proteins and funded the SOMAscan assays. Joni V. Lindbohm and Pyry N. Sipila have received personal lecture fees from the University of Helsinki. Nina Mars reports no conflicts of interest. Keenan A. Walker reports personal lecture fee from the Boston University Medical Center and holds the Programming Chair at the National Academy of Neuropsychology. Eric J. Brunner reports Osaka University research capacity building grant paid to employer. Archana Singh‐Manoux reports no conflicts of interest. Gill Livingston reports no conflicts of interest. Kalle Saksela reports no conflicts of interest. Jane E. Ferrie reports no conflicts of interest. Ruth C. Lovering reports personal lecture fees from the University College London, funding from a COST action grant, and is a member of the executive committee for the International Society of Biocuration (a voluntary role and no payment has been or will be made). Stephen A. Williams is employee of SomaLogic Inc., which has a commercial interest in the results and co‐inventor on multiple patents for specific proteomic models of disease. None of these patents relate to dementia (the topic of the manuscript). Aroon D. Hingorani reports no conflicts of interest. Rebecca F. Gottesman reports personal lecture fees for speaking at University of Michigan grand rounds, University of Alabama McKnight lecture, and the American College of Cardiology conference. Rebecca F. Gottesman is the secretary for the American Neurological Association. Henrik Zetterberg reports that he has served on the scientific advisory boards for Denali, Roche Diagnostics, Wave, Samumed, Siemens Healthineers, Pinteon Therapeutics, and CogRx; has given lectures in symposia sponsored by Fujirebio, Alzecure, and Biogen; and is a co‐founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program. Henrik Zetterberg is also the chair of the Alzheimer's Association Global Biomarker Standardization Consortium and the Alzheimer's Association Biolfluid‐Based Biomarker Professional Interest Area. Mika Kivimaki reports no conflicts of interest.

Figures

**FIGURE 1**
Flowchart of sample selection in discovery and validation cohorts. ARIC, the Atherosclerosis Risk in Communities study

**FIGURE 2**
Proteins associated with dementia in Whitehall II and ARIC cohorts. HR, hazard ratio; 95% CI, 95% confidence interval; ARIC, the Atherosclerosis Risk in Communities study; SD, standard deviation; FDR, false discovery rate of 5%; Protein names: N‐terminal pro‐BNP, N‐terminal pro‐BNP; CDCP1, CUB domain‐containing protein 1. MIC‐1, growth/differentiation factor 15. CRDL1, Chordin‐like protein 1; RNAS6, ribonuclease K6; SAP3, ganglioside GM2 activator; HE4, WAP four‐disulfide core domain protein 2; TIMP‐4, metalloproteinase inhibitor 4; IGFBP‐7, insulin‐like growth factor‐binding protein 7; OPG, tumor necrosis factor receptor superfamily member 11B; Siglec‐7, sialic acid‐binding Ig‐like lectin 7; SVEP1, Sushi, von Willebrand factor type A, EGF and pentraxin domain‐containing protein 1; TREM2, triggering receptor expressed on myeloid cells 2; NPS‐PLA2, phospholipase A2, membrane associated; MARCKSL1, MARCKS‐related protein; Spondin‐1, spondin‐1; IGFBP‐2, insulin‐like growth factor‐binding protein 2; Neuropeptide W, neuropeptide W; ST4S6, Carbohydrate sulfotransferase 15; TPPP2, tubulin polymerization‐promoting protein family member 2; LEAP‐1, hepcidin

**FIGURE 3**
Expression profile of the genes coding the 15 proteins associated with rate of cognitive decline and dementia derived from Genotype‐Tissue Expression (GTEx) database. Y‐axis shows the extent to which these genes are expressed by the organs and tissues listed in X‐axis. For clarity, tissues in the brain are marked in bold. EBV, Ebstein‐Barr virus; TPM, transcripts per million

See this image and copyright information in PMC

References

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Plasma proteins, cognitive decline, and 20-year risk of dementia in the Whitehall II and Atherosclerosis Risk in Communities studies

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Plasma proteins, cognitive decline, and 20-year risk of dementia in the Whitehall II and Atherosclerosis Risk in Communities studies

Authors

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Abstract

Conflict of interest statement

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