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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

View ORCID ProfileKevin J. Sullivan, Chad Blackshear, Jeannette Simino, View ORCID ProfileAdrienne Tin, Keenan A. Walker, A. Richey Sharrett, View ORCID ProfileSteven Younkin, Rebecca F. Gottesman, View ORCID ProfileMichelle 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
Kevin J. Sullivan
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.
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Chad Blackshear
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.
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Jeannette Simino
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.
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Adrienne Tin
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.
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  • ORCID record for Adrienne Tin
Keenan A. Walker
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.
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A. Richey Sharrett
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.
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Steven Younkin
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.
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Rebecca F. Gottesman
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.
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Michelle M. Mielke
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.
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  • ORCID record for Michelle M. Mielke
David Knopman
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.
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B. Gwen Windham
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.
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Michael E. Griswold
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.
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Thomas H. Mosley
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.
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Citation
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
Neurology Sep 2021, 97 (11) e1123-e1131; DOI: 10.1212/WNL.0000000000012482

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Abstract

Background and Objectives To evaluate the association between midlife plasma amyloid-β (Aβ1-42, Aβ1-40, Aβ42:Aβ40) and risk of mild cognitive impairment (MCI) and dementia.

Methods Plasma Aβ42 and Aβ40 were retrospectively measured with a fluorometric bead-based immunoassay in a subsample of the Atherosclerosis Risk in Communities cohort study. We investigated the relationship of plasma Aβ42, Aβ40, and Aβ42:Aβ40 ratio measured in midlife and late life and the change from midlife to late life to risk of MCI, dementia, and combined MCI/dementia outcomes in late life (from 2011–2019). We used multinomial logistic regressions estimating relative risk ratios (RRRs) of these cognitive outcomes vs cognitively normal adjusted for age, sex, education, site-race, APOE, hypertension, diabetes, and body mass index.

Results A total of 2,284 participants were included (midlife mean age 59.2 ± 5.2, 57% female, 22% Black). Each doubling of midlife Aβ42:Aβ40 was associated with 37% lower risk of MCI/dementia (RRR 0.63, 95% confidence interval [CI] 0.46–0.87), but only up to approximately the median (spline model threshold 0.20). Every 1-SD increase in plasma Aβ42 (10 pg/mL) was associated with 13% lower risk of MCI/dementia (RRR 0.87, 95% CI 0.77–0.98), whereas every 1-SD increase in plasma Aβ40 (67 pg/mL) was associated with 15% higher risk of MCI/dementia (RRR 1.15, 95% CI 1.01–1.29). Associations were comparable but slightly weaker statistically when models were repeated using late-life plasma Aβ predictors. Aβ42 and Aβ40 increased from midlife to late life, but changes were not associated with cognitive outcomes.

Discussion Midlife measurement of plasma Aβ may have utility as a blood-based biomarker indicative of risk for future cognitive impairment.

Glossary

Aβ=
amyloid-β;
AD=
Alzheimer disease;
ARIC=
Atherosclerosis Risk in Communities;
BMI=
body mass index;
CI=
confidence interval;
MCI=
mild cognitive impairment;
MMSE=
Mini-Mental State Examination;
RRR=
relative risk ratio

Footnotes

  • Go to Neurology.org/N for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article.

  • Received December 17, 2020.
  • Accepted in final form June 16, 2021.
  • 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.
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