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September 14, 2021; 97 (11) Research Article

Association of Midlife Plasma Amyloid-β Levels With Cognitive Impairment in Late Life

The ARIC Neurocognitive Study

Kevin J. Sullivan, Chad Blackshear, Jeannette Simino, Adrienne Tin, Keenan A. Walker, A. Richey Sharrett, Steven Younkin, Rebecca F. Gottesman, Michelle M. Mielke, David Knopman, B. Gwen Windham, Michael E. Griswold, Thomas H. Mosley
First published August 4, 2021, DOI: https://doi.org/10.1212/WNL.0000000000012482
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Article Information

vol. 97 no. 11 e1123-e1131
DOI: 
https://doi.org/10.1212/WNL.0000000000012482
PubMed: 
34349010
Published By: 
Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology
Print ISSN: 
0028-3878
Online ISSN: 
1526-632X
History: 
  • Received December 17, 2020
  • Accepted in final form June 16, 2021
  • First Published August 4, 2021.

Article Versions

Copyright & Usage: 
Written work prepared by employees of the Federal Government as part of their official duties is, under the U.S. Copyright Act, a “work of the United States Government” for which copyright protection under Title 17 of the United States Code is not available. As such, copyright does not extend to the contributions of employees of the Federal Government.

Author Disclosures

    1. Kevin J. Sullivan, PhD, MPH,
    2. Chad Blackshear, MS,
    3. Jeannette Simino, PhD,
    4. Adrienne Tin, PhD,
    5. Keenan A. Walker, PhD,
    6. A. Richey Sharrett, MD, DrPH,
    7. Steven Younkin, MD, PhD,
    8. Rebecca F. Gottesman, MD, PhD,
    9. Michelle M. Mielke, PhD,
    10. David Knopman, MD,
    11. B. Gwen Windham, MD,
    12. Michael E. Griswold, PhD and
    13. Thomas H. Mosley, PhD
  1. Kevin J. Sullivan, PhD, MPH,
    2. Scientific Advisory Boards:

    1. NONE

    Gifts:

    1. NONE

    Funding for Travel or Speaker Honoraria:

    1. NONE

    Editorial Boards:

    1. NONE

    Patents:

    1. NONE

    Publishing Royalties:

    1. NONE

    Employment, Commercial Entity:

    1. NONE

    Consultancies:

    1. NONE

    Speakers' Bureaus:

    1. NONE

    Other Activities:

    1. NONE

    Clinical Procedures or Imaging Studies:

    1. NONE

    Research Support, Commercial Entities:

    1. NONE

    Research Support, Government Entities:

    1. NONE

    Research Support, Academic Entities:

    1. NONE

    Research Support, Foundations and Societies:

    1. NONE

    Stock/Stock Options/Board of Directors Compensation:

    1. NONE

    License Fee Payments, Technology or Inventions:

    1. NONE

    Royalty Payments, Technology or Inventions:

    1. NONE

    Stock/Stock Options, Research Sponsor:

    1. NONE

    Stock/Stock Options, Medical Equipment & Materials:

    1. NONE

    Legal Proceedings:

    1. NONE

  2. Chad Blackshear, MS,
    3. Scientific Advisory Boards:

    1. NONE

    Gifts:

    1. NONE

    Funding for Travel or Speaker Honoraria:

    1. NONE

    Editorial Boards:

    1. NONE

    Patents:

    1. NONE

    Publishing Royalties:

    1. NONE

    Employment, Commercial Entity:

    1. NONE

    Consultancies:

    1. NONE

    Speakers' Bureaus:

    1. NONE

    Other Activities:

    1. NONE

    Clinical Procedures or Imaging Studies:

    1. NONE

    Research Support, Commercial Entities:

    1. NONE

    Research Support, Government Entities:

    1. NONE

    Research Support, Academic Entities:

    1. NONE

    Research Support, Foundations and Societies:

    1. NONE

    Stock/Stock Options/Board of Directors Compensation:

    1. NONE

    License Fee Payments, Technology or Inventions:

    1. NONE

    Royalty Payments, Technology or Inventions:

    1. NONE

    Stock/Stock Options, Research Sponsor:

    1. NONE

    Stock/Stock Options, Medical Equipment & Materials:

    1. NONE

    Legal Proceedings:

    1. NONE

  3. Jeannette Simino, PhD,
    4. Scientific Advisory Boards:

    1. NONE

    Gifts:

    1. NONE

    Funding for Travel or Speaker Honoraria:

    1. NONE

    Editorial Boards:

    1. NONE

    Patents:

    1. NONE

    Publishing Royalties:

    1. NONE

    Employment, Commercial Entity:

    1. NONE

    Consultancies:

    1. NONE

    Speakers' Bureaus:

    1. NONE

    Other Activities:

    1. NONE

    Clinical Procedures or Imaging Studies:

    1. NONE

    Research Support, Commercial Entities:

    1. NONE

    Research Support, Government Entities:

    1. (1) NHLBI Grant R01:HL142003 Role: Subaward PI Duration: May 2018 –April 2021 (2)NIH/NIA 1RF1AG059421-01 Role: Biostatistician Duration: January 2019-June 2023

    Research Support, Academic Entities:

    1. (1)Memory Impairment and Neurodegenerative Dementia (MIND) Center

    Research Support, Foundations and Societies:

    1. NONE

    Stock/Stock Options/Board of Directors Compensation:

    1. NONE

    License Fee Payments, Technology or Inventions:

    1. NONE

    Royalty Payments, Technology or Inventions:

    1. NONE

    Stock/Stock Options, Research Sponsor:

    1. NONE

    Stock/Stock Options, Medical Equipment & Materials:

    1. NONE

    Legal Proceedings:

    1. NONE

  4. Adrienne Tin, PhD,
    5. Scientific Advisory Boards:

    1. NONE

    Gifts:

    1. NONE

    Funding for Travel or Speaker Honoraria:

    1. NONE

    Editorial Boards:

    1. NONE

    Patents:

    1. NONE

    Publishing Royalties:

    1. NONE

    Employment, Commercial Entity:

    1. NONE

    Consultancies:

    1. NONE

    Speakers' Bureaus:

    1. NONE

    Other Activities:

    1. NONE

    Clinical Procedures or Imaging Studies:

    1. NONE

    Research Support, Commercial Entities:

    1. NONE

    Research Support, Government Entities:

    1. NIAMS, R01AR073178, PI, 2018-2023

    Research Support, Academic Entities:

    1. NONE

    Research Support, Foundations and Societies:

    1. NONE

    Stock/Stock Options/Board of Directors Compensation:

    1. NONE

    License Fee Payments, Technology or Inventions:

    1. NONE

    Royalty Payments, Technology or Inventions:

    1. NONE

    Stock/Stock Options, Research Sponsor:

    1. NONE

    Stock/Stock Options, Medical Equipment & Materials:

    1. NONE

    Legal Proceedings:

    1. NONE

  5. Keenan A. Walker, PhD,
    6. Scientific Advisory Boards:

    1. NONE

    Gifts:

    1. NONE

    Funding for travel or speaker honoraria:

    1. Speaker honoraria from Boston University Medical Center, personal payment

    Editorial Boards:

    1. Neuropsychology, consulting editor, 2019 - present

    Patents:

    1. NONE

    Publishing Royalties:

    1. NONE

    Employment, Commercial Entity:

    1. NONE

    Consultancies:

    1. NONE

    Speakers' Bureaus:

    1. NONE

    Other Activities:

    1. NONE

    Clinical Procedures or Imaging Studies:

    1. NONE

    Research Support, Commercial Entities:

    1. NONE

    Research Support, Government Entities:

    1. NIH, National Institute on Aging, K23 AG064122 NIH, National Institute on Aging, Intramural Research Program.

    Research Support, Academic Entities:

    1. NONE

    Research Support, Foundations and Societies:

    1. NONE

    Stock/Stock Options/Board of Directors Compensation:

    1. NONE

    License Fee Payments, Technology or Inventions:

    1. NONE

    Royalty Payments, Technology or Inventions:

    1. NONE

    Stock/Stock Options, Research Sponsor:

    1. NONE

    Stock/Stock Options, Medical Equipment & Materials:

    1. NONE

    Legal Proceedings:

    1. NONE

  6. A. Richey Sharrett, MD, DrPH,
    7. Scientific Advisory Boards:

    1. NONE

    Gifts:

    1. NONE

    Funding for Travel or Speaker Honoraria:

    1. NONE

    Editorial Boards:

    1. NONE

    Patents:

    1. NONE

    Publishing Royalties:

    1. NONE

    Employment, Commercial Entity:

    1. NONE

    Consultancies:

    1. NONE

    Speakers' Bureaus:

    1. NONE

    Other Activities:

    1. NONE

    Clinical Procedures or Imaging Studies:

    1. NONE

    Research Support, Commercial Entities:

    1. NONE

    Research Support, Government Entities:

    1. NHLBI HL 96812, Co-Investigator 2015-19 NIA, AG 40282, Co-Investigator 2016-22;AG 50745 2016-21 NHLBI HHSN2682017, Co-Investigator 2016-21 NIA AG55426, Co-Investigator 2017-22; AG 52412, 2016-20

    Research Support, Academic Entities:

    1. Professor, Johns Hopkins Bloomberg School of Public Health

    Research Support, Foundations and Societies:

    1. NONE

    Stock/Stock Options/Board of Directors Compensation:

    1. NONE

    License Fee Payments, Technology or Inventions:

    1. NONE

    Royalty Payments, Technology or Inventions:

    1. NONE

    Stock/Stock Options, Research Sponsor:

    1. NONE

    Stock/Stock Options, Medical Equipment & Materials:

    1. NONE

    Legal Proceedings:

    1. NONE

  7. Steven Younkin, MD, PhD,
    8. Scientific Advisory Boards:

    1. NONE

    Gifts:

    1. NONE

    Funding for Travel or Speaker Honoraria:

    1. NONE

    Editorial Boards:

    1. NONE

    Patents:

    1. NONE

    Publishing Royalties:

    1. NONE

    Employment, Commercial Entity:

    1. NONE

    Consultancies:

    1. NONE

    Speakers' Bureaus:

    1. NONE

    Other Activities:

    1. NONE

    Clinical Procedures or Imaging Studies:

    1. NONE

    Research Support, Commercial Entities:

    1. NONE

    Research Support, Government Entities:

    1. NONE

    Research Support, Academic Entities:

    1. NONE

    Research Support, Foundations and Societies:

    1. NONE

    Stock/Stock Options/Board of Directors Compensation:

    1. NONE

    License Fee Payments, Technology or Inventions:

    1. NONE

    Royalty Payments, Technology or Inventions:

    1. Royalty payments from Mayo for licensing of Tg2576 mouse model of AD (∼1998-present)

    Stock/Stock Options, Research Sponsor:

    1. NONE

    Stock/Stock Options, Medical Equipment & Materials:

    1. NONE

    Legal Proceedings:

    1. NONE

  8. Rebecca F. Gottesman, MD, PhD,
    9. Scientific Advisory Boards:

    1. NONE

    Gifts:

    1. NONE

    Funding for Travel or Speaker Honoraria:

    1. NONE

    Editorial Boards:

    1. Neurology, Associate Editor, 2015-2020

    Patents:

    1. NONE

    Publishing Royalties:

    1. NONE

    Employment, Commercial Entity:

    1. NONE

    Consultancies:

    1. NONE

    Speakers' Bureaus:

    1. NONE

    Other Activities:

    1. NONE

    Clinical Procedures or Imaging Studies:

    1. NONE

    Research Support, Commercial Entities:

    1. Florbetapir isotope (18F-AV-45) provided for investigator-initiated research by Avid Radiopharmaceuticals, a wholly owned subsidiary of Eli Lilly.

    Research Support, Government Entities:

    1. National Institutes of Health/ National Institute on Aging. 1R01AG040282, Principal Investigator, 9/2011-8/2021 RF1 AG050745, Multiple Principal Investigator, 4/2016-3/2021 NIH/NIH K24 AG052573, Principal Investigator NIH (NHLBI/NIA/NINDS) U01 HL096812, Principal Investigator, 12/1/2019- 11/30/2023

    Research Support, Academic Entities:

    1. NONE

    Research Support, Foundations and Societies:

    1. NONE

    Stock/Stock Options/Board of Directors Compensation:

    1. NONE

    License Fee Payments, Technology or Inventions:

    1. NONE

    Royalty Payments, Technology or Inventions:

    1. NONE

    Stock/Stock Options, Research Sponsor:

    1. NONE

    Stock/Stock Options, Medical Equipment & Materials:

    1. NONE

    Legal Proceedings:

    1. NONE

  9. Michelle M. Mielke, PhD,
    10. Scientific Advisory Boards:

    1. NONE

    Gifts:

    1. NONE

    Funding for Travel or Speaker Honoraria:

    1. NONE

    Editorial Boards:

    1. Alzheimer's and Dementia: The Journal of the Alzheimer Association, Senior associate editor, 2012-present Journal of Alzheimer Disease, Senior editor, 2012- present Neurology, Editorial Board Member, 2020-present

    Patents:

    1. NONE

    Publishing Royalties:

    1. NONE

    Employment, Commercial Entity:

    1. NONE

    Consultancies:

    1. Brain Protection Company Biogen

    Speakers' Bureaus:

    1. NONE

    Other Activities:

    1. NONE

    Clinical Procedures or Imaging Studies:

    1. NONE

    Research Support, Commercial Entities:

    1. NONE

    Research Support, Government Entities:

    1. Dr. Mielke was funded by the following NIH grants: R01 AG049704 U01 AG006786 RF1 AG055151 U54 AG44174

    Research Support, Academic Entities:

    1. NONE

    Research Support, Foundations and Societies:

    1. NONE

    Stock/Stock Options/Board of Directors Compensation:

    1. NONE

    License Fee Payments, Technology or Inventions:

    1. NONE

    Royalty Payments, Technology or Inventions:

    1. NONE

    Stock/Stock Options, Research Sponsor:

    1. NONE

    Stock/Stock Options, Medical Equipment & Materials:

    1. NONE

    Legal Proceedings:

    1. NONE

  10. David Knopman, MD,
    11. Scientific Advisory Boards:

    1. DIAN study DSMB (Sept 2013 - July 2019; August 2020 - present). Dr. Knopman serves on a Data Safety monitoring Board for a tau therapeutic for Biogen, but receives no personal compensation. He served as a consultant for Samus Therapeutics, Third Rock, Roche and Alzeca Biosciences but receives no personal compensation.

    Gifts:

    1. NONE

    Funding for Travel or Speaker Honoraria:

    1. NONE

    Editorial Boards:

    1. Omsbudsman Neurology, previously; Scientific Integrity officer, currently

    Patents:

    1. NONE

    Publishing Royalties:

    1. NONE

    Employment, Commercial Entity:

    1. NONE

    Consultancies:

    1. NONE

    Speakers' Bureaus:

    1. NONE

    Other Activities:

    1. NONE

    Clinical Procedures or Imaging Studies:

    1. NONE

    Research Support, Commercial Entities:

    1. (1) A4 clinical trial partially funded by Lilly (site PI) (2) Biogen Alzheimer Study (site PI)

    Research Support, Government Entities:

    1. NIH: R01-AG11378 ongoing, R01 AG41851; P30-AG 62677 (Mayo Alzheimer’s Disease Research Center) ongoing, U01 AG 06786 (Mayo Alzheimer Disease Patient Registry) ongoing. 1U01HL096917 ARIC Dementia Study. AG 037551 Chronic Kidney Disease and Cognitive functioning.

    Research Support, Academic Entities:

    1. NONE

    Research Support, Foundations and Societies:

    1. NONE

    Stock/Stock Options/Board of Directors Compensation:

    1. NONE

    License Fee Payments, Technology or Inventions:

    1. NONE

    Royalty Payments, Technology or Inventions:

    1. NONE

    Stock/Stock Options, Research Sponsor:

    1. NONE

    Stock/Stock Options, Medical Equipment & Materials:

    1. NONE

    Legal Proceedings:

    1. NONE

  11. B. Gwen Windham, MD,
    12. Scientific Advisory Boards:

    1. NONE

    Gifts:

    1. NONE

    Funding for Travel or Speaker Honoraria:

    1. NONE

    Editorial Boards:

    1. NONE

    Patents:

    1. NONE

    Publishing Royalties:

    1. NONE

    Employment, Commercial Entity:

    1. NONE

    Consultancies:

    1. NONE

    Speakers' Bureaus:

    1. NONE

    Other Activities:

    1. NONE

    Clinical Procedures or Imaging Studies:

    1. NONE

    Research Support, Commercial Entities:

    1. NONE

    Research Support, Government Entities:

    1. (1) NIH/NIA 5R01AG054787 Principal Investigator 2018-2022 (2) NIH/NIA 5R01HL126637 Subcontract Co-Investigator 2016- 2021 (3) NIH/NHLBI HHSN268201700004I, Co-investigator 2017-2021 (4)NIH/NHLBI/NINDS/NIA 2U01HL096812-09, Co- investigator 2010-2023 (5) NIH/NHLBI 1R01HL126637, subcontract Co-investigator 2016-2021 (6) NIH/NHLBI 1R01HL1311136 subcontract Co-investigator 2016-2020 (4) NIA 5R21AG059068-02 Subcontract PI 2018-2020 (5) NIH/NHLBI HHSN268201800010I Co-Investigator 2019-2022 (6) NIH/NHLBI 5R01HL131136 Co-investigator 2016-2020 (7) NIH/NIA R01AG066134 Co-investigator 2019-2024

    Research Support, Academic Entities:

    1. NONE

    Research Support, Foundations and Societies:

    1. The Memory Impairment and Neurodegenerative Dementia (MIND) Center

    Stock/Stock Options/Board of Directors Compensation:

    1. NONE

    License Fee Payments, Technology or Inventions:

    1. NONE

    Royalty Payments, Technology or Inventions:

    1. NONE

    Stock/Stock Options, Research Sponsor:

    1. NONE

    Stock/Stock Options, Medical Equipment & Materials:

    1. NONE

    Legal Proceedings:

    1. NONE

  12. Michael E. Griswold, PhD and
    13. Scientific Advisory Boards:

    1. NONE

    Gifts:

    1. NONE

    Funding for Travel or Speaker Honoraria:

    1. NONE

    Editorial Boards:

    1. NONE

    Patents:

    1. NONE

    Publishing Royalties:

    1. NONE

    Employment, Commercial Entity:

    1. NONE

    Consultancies:

    1. NONE

    Speakers' Bureaus:

    1. NONE

    Other Activities:

    1. NONE

    Clinical Procedures or Imaging Studies:

    1. NONE

    Research Support, Commercial Entities:

    1. NONE

    Research Support, Government Entities:

    1. The Atherosclerosis Risk in Communities Study is carried out as a collaborative study supported by National Heart, Lung, and Blood Institute contracts (HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, and HHSN268201100012C). Neurocognitive data is collected by 2U01HL096812, 2U01HL096814, 2U01HL096899, 2U01HL096902, 2U01HL096917 from the NIH (NHLBI, NINDS, NIA and NIDCD). Biostatistician, 2012-2018

    Research Support, Academic Entities:

    1. NONE

    Research Support, Foundations and Societies:

    1. NONE

    Stock/Stock Options/Board of Directors Compensation:

    1. NONE

    License Fee Payments, Technology or Inventions:

    1. NONE

    Royalty Payments, Technology or Inventions:

    1. NONE

    Stock/Stock Options, Research Sponsor:

    1. NONE

    Stock/Stock Options, Medical Equipment & Materials:

    1. NONE

    Legal Proceedings:

    1. NONE

  13. Thomas H. Mosley, PhD
    14. Scientific Advisory Boards:

    1. NONE

    Gifts:

    1. NONE

    Funding for Travel or Speaker Honoraria:

    1. NONE

    Editorial Boards:

    1. NONE

    Patents:

    1. NONE

    Publishing Royalties:

    1. NONE

    Employment, Commercial Entity:

    1. NONE

    Consultancies:

    1. NONE

    Speakers' Bureaus:

    1. NONE

    Other Activities:

    1. NONE

    Clinical Procedures or Imaging Studies:

    1. NONE

    Research Support, Commercial Entities:

    1. NONE

    Research Support, Government Entities:

    1. 1) NIH, HHSN268201100010C, PI, 11/2010 - 11/2016 2) NIH, U01HL096917, PI, 07/2010-04/2014 3) NIH, R01HL103695, site PI, investigator, 04/2011- 03/2015 4) NIH, R01HL105626, site PI,09/2011-06/2015 5) NIH, R01AG040282, site PI, 09/2011-05/2016 6) NIH, U01CA164975, site PI, 05/2012-04/2017 7) NIH, R01HL116900, site PI, 08/2013-07/2017

    Research Support, Academic Entities:

    1. NONE

    Research Support, Foundations and Societies:

    1. NONE

    Stock/Stock Options/Board of Directors Compensation:

    1. NONE

    License Fee Payments, Technology or Inventions:

    1. NONE

    Royalty Payments, Technology or Inventions:

    1. NONE

    Stock/Stock Options, Research Sponsor:

    1. NONE

    Stock/Stock Options, Medical Equipment & Materials:

    1. NONE

    Legal Proceedings:

    1. NONE

  1. From the Departments of Medicine (K.J.S., A.T., B.G.W., M.E.G., T.H.M.) and Data Science (C.S., J.S.), University of Mississippi Medical Center, Jackson; Departments of Neurology (K.A.W.) and Epidemiology (A.R.S.), The Johns Hopkins University, Baltimore, MD; Mayo Clinic (S.Y.), Jacksonville, FL; Stroke Branch (R.F.G.), National Institute of Neurological Disorders and Stroke Intramural Program, National Institutes of Health, Bethesda, MD; and Departments of Health Sciences Research (M.M.M.) and Neurology (M.M.M., D.K.), Mayo Clinic, Rochester, MN.
  1. Correspondence
    Dr. Sullivan ksullivan3{at}umc.edu
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