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.
| Original language | English (US) |
|---|---|
| Journal | Alzheimer's and Dementia |
| DOIs | |
| State | Accepted/In press - 2021 |
| Externally published | Yes |
Keywords
- cognitive decline
- cohort study
- dementia
- longitudinal study
- proteomics
ASJC Scopus subject areas
- Epidemiology
- Health Policy
- Developmental Neuroscience
- Clinical Neurology
- Geriatrics and Gerontology
- Psychiatry and Mental health
- Cellular and Molecular Neuroscience
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Plasma proteins, cognitive decline, and 20-year risk of dementia in the Whitehall II and Atherosclerosis Risk in Communities studies. / Lindbohm, Joni V.; Mars, Nina; Walker, Keenan A.; Singh-Manoux, Archana; Livingston, Gill; Brunner, Eric J.; Sipilä, Pyry N.; Saksela, Kalle; Ferrie, Jane E.; Lovering, Ruth C.; Williams, Stephen A.; Hingorani, Aroon D.; Gottesman, Rebecca F.; Zetterberg, Henrik; Kivimäki, Mika.
In: Alzheimer's and Dementia, 2021.Research output: Contribution to journal › Article › peer-review
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TY - JOUR
T1 - Plasma proteins, cognitive decline, and 20-year risk of dementia in the Whitehall II and Atherosclerosis Risk in Communities studies
AU - Lindbohm, Joni V.
AU - Mars, Nina
AU - Walker, Keenan A.
AU - Singh-Manoux, Archana
AU - Livingston, Gill
AU - Brunner, Eric J.
AU - Sipilä, Pyry N.
AU - Saksela, Kalle
AU - Ferrie, Jane E.
AU - Lovering, Ruth C.
AU - Williams, Stephen A.
AU - Hingorani, Aroon D.
AU - Gottesman, Rebecca F.
AU - Zetterberg, Henrik
AU - Kivimäki, Mika
N1 - Funding Information: We thank Jocelyn Jingsha Chen for helping in data analysis of the ARIC study. The study was supported by the UK Medical Research Council (S011676, K013351, R024227), the Wellcome Trust (221854/Z/20/Z), the National Institute on Aging (National Institutes of Health; R01AG056477 and R01AG062553), the British Heart Foundation (RG/16/11/32334), the Academy of Finland (311492), and NordForsk (75021). The Atherosclerosis Risk in Communities study has been funded in whole or in part with federal funds from the National Heart, Lung, and Blood Institute; National Institutes of Health; Department of Health and Human Services (contract numbers HHSN268201700001I, HHSN268201700002I, HHSN268201700003I, HHSN268201700004I and HHSN268201700005I), R01HL087641, R01HL086694; National Human Genome Research Institute contract U01HG004402; and National Institutes of Health contract HHSN268200625226C. Neurocognitive data collection was supported by U01 2U01HL096812, 2U01HL096814, 2U01HL096899, 2U01HL096902, 2U01HL096917 from the NIH (NHLBI, NINDS, NIA, and NIDCD). ARIC infrastructure was partially supported by grant number UL1RR025005, a component of the National Institutes of Health and NIH Roadmap for Medical Research. University College London and Johns Hopkins University have signed a collaboration agreement with SomaLogic, Inc to conduct SOMAscan of Whitehall and ARIC stored samples at no charge in exchange for the rights to analyze linked Whitehall and ARIC phenotype data. The Genotype‐Tissue Expression (GTEx) Project was supported by the Common Fund of the Office of the Director of the National Institutes of Health, and by the following institutes: NCI, NHGRI, NHLBI, NIDA, NIMH, and NINDS. Joni V. Lindbohm was supported by Academy of Finland (311492) and Helsinki Institute of Life Science (H970) grants paid to employer. Nina Mars was supported by the Academy of Finland (grant number 331671) paid to employer. Keenan A. Walker and Rebecca F. Gottesman were supported by contracts K23 AG064122 and K24 AG052573 from NIH/NIA paid to employer. Archana Singh‐Manoux was supported by the National Institute on Aging, NIH (R01AG062553;R01AG056477) grants paid to employer. Gill Livingston was supported by all to institution Wellcome collaborative grant (UNS114095), Alzheimer's Society PhD fellowship AS‐PhD‐19a‐006 NIHR HTA grant, NIHR128761 NIHR ARC PhD 1861414, NIHR senior investigator NIHR201321 NIHR HTA Project: 16/155/01 RPGF1711∖10, Dunhill Medical Trust Alzheimer's society 367 (AS‐IGF ‐16‐001), HTA 15/161/05 Wellcome Research Training Fellowship 200163/Z/15/Z AS‐SF‐15‐005, and Alzheimer's Society Senior Fellowship AS‐SF‐18b‐001. All grants were paid to employer. Eric J. Brunner was supported by the UK Medical Research Council, Economic and Social Research Council (ES/T014377/1), and UK‐China Health And Social Challenges Ageing Project (UKCHASCAP): present and future burden of dementia, and policy responses. All grants were paid to employer. Pyry N. Sipila was supported by Academy of Finland (311492 and 329202), NordForsk (75021), Helsinki Institute of Life Science (H970), and Finnish Foundation for Alcohol Studies grants paid to employer. Kalle Saksela reports no financial support. Jane E. Ferrie reports no financial support. Ruth C. Lovering was supported by Alzheimer's Research UK grant ARUK‐NAS2017A‐1 paid to employer. Stephen A. Williams is employed by SomaLogic inc. Aroon D. Hingorani was supported by NIHR Senior Investigator Competition, UKRI‐NIHR Strategic Priority Fund Multimorbidity Mechanisms, and Therapeutics Research Collaborative and the Wellcome Trust (221854/Z/20/Z) grants paid to employer. Henrik Zetterberg was a Wallenberg Scholar supported by grants from the Swedish Research Council (2018‐02532), the European Research Council (681712), Swedish State Support for Clinical Research (ALFGBG‐720931), the Alzheimer Drug Discovery Foundation, USA (201809‐2016862), and the UK Dementia Research Institute at University College London. All grants were paid to employer. Mika Kivimaki was supported by the Wellcome Trust (221854/Z/20/Z), the UK Medical Research Council (MR/S011676, MR/R024227), the National Institute on Aging (R01AG062553, R01AG056477), the Academy of Finland (311492, 329202), Helsinki Institute of Life Science (H970), NordForsk (75021), and the Finnish Work Environment Fund (190424). All grants were paid to employer. Funding Information: 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. Publisher Copyright: © 2021 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.
PY - 2021
Y1 - 2021
N2 - 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.
AB - 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.
KW - cognitive decline
KW - cohort study
KW - dementia
KW - longitudinal study
KW - proteomics
UR - http://www.scopus.com/inward/record.url?scp=85111653305&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85111653305&partnerID=8YFLogxK
U2 - 10.1002/alz.12419
DO - 10.1002/alz.12419
M3 - Article
C2 - 34338426
AN - SCOPUS:85111653305
JO - Alzheimer's and Dementia
JF - Alzheimer's and Dementia
SN - 1552-5260
ER -