Association of Midlife Plasma Amyloid-β Levels With Cognitive Impairment in Late Life: The ARIC Neurocognitive Study

Affiliations

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. ksullivan3@umc.edu.
² 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.

PMID: 34349010
PMCID: PMC8456355
DOI: 10.1212/WNL.0000000000012482

Association of Midlife Plasma Amyloid-β Levels With Cognitive Impairment in Late Life: The ARIC Neurocognitive Study

Kevin J Sullivan et al. Neurology. 2021.

. 2021 Sep 14;97(11):e1123-e1131.

doi: 10.1212/WNL.0000000000012482. Epub 2021 Aug 4.

Affiliations

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. ksullivan3@umc.edu.
² 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.

PMID: 34349010
PMCID: PMC8456355
DOI: 10.1212/WNL.0000000000012482

Abstract

Background and objectives: To evaluate the association between midlife plasma amyloid-β (Aβ_1-42, Aβ_1-40, 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.

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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Figures

**Figure 1. Midlife and Late-Life Plasma Aβ Distributions and Scatterplots Concurrently and Cross-Temporally**
Graphs display histograms of plasma amyloid-β (Aβ) distributions (picograms per milliliter or ratio) at midlife and late life. Change scores (midlife − late life; picograms per milliliter) reflect increases in Aβ₄₂ and Aβ₄₀ from midlife to late life. Individual observations are plotted with a lowess smoother and kernel density plots representing quartiles 1, 2 (median), and 3 of the data. Forty-six observations with Aβ₄₂ or Aβ₄₀ values exceeding 70 or 500 pg/mL, respectively, were removed for enhanced visualization. Ratio distributions in panel A have been log₂ transformed to approximate normality. (A) Late-life and midlife plasma Aβ₄₂:Aβ₄₀; correlation 0.487. (B) Late-life and midlife plasma Aβ₄₂ (picograms per milliliter); correlation 0.486. (C) Late-life and midlife plasma Aβ₄₀ (picograms per milliliter); correlation 0.313. (D) Midlife plasma Aβ₄₂ (picograms per milliliter) and Aβ₄₀ (picograms per milliliter); correlation 0.612. (E) Late-life plasma Aβ₄₂ (picograms per milliliter) and Aβ₄₀ (picograms per milliliter); correlation 0.470. (F) Change in plasma Aβ₄₂ (picograms per milliliter) and plasma Aβ₄₀ (picograms per milliliter); correlation 0.612.

**Figure 2. Midlife (Visit 3) Plasma Aβ Associations With Visit 7 MCI/Dementia Probabilities**
Relative risk ratio (RRRs; normal referent) given with 95% confidence limits. Histograms display the midlife distributions of amyloid-β₄₂ (Aβ₄₂):Aβ₄₀, Aβ₄₂, and Aβ₄₀. Two observations with Aβ₄₂ or Aβ₄₀ values exceeding 70 or 500 pg/mL, respectively, were removed for enhanced visualization. (A) Each doubling of Aβ₄₂:Aβ₄₀ when Aβ₄₂:Aβ₄₀ is ≤0.20 was associated with an RRR of mild cognitive impairment (MCI)/dementia vs normal of 0.63 (p = 0.005). Each doubling of Aβ₄₂:Aβ₄₀ when Aβ₄₂:Aβ₄₀ is >0.2 was associated with an RRR of MCI/dementia vs normal of 0.97 (p = 0.813). (B) Each 1-SD-higher Aβ₄₂ (10 pg/mL) across the entire spectrum of Aβ₄₂ was associated with an RRR of MCI/dementia vs normal of 0.87 (p = 0.026). (C) Each 1-SD-higher Aβ₄₀ (67 pg/mL) across the entire spectrum of Aβ₄₀ was associated with an RRR of MCI/dementia vs normal of 1.15 (p = 0.030).

**Figure 3. Midlife (Visit 3) and Late-Life (Visit 5) Plasma Aβ Associations With Visit 7 Cognitive Status**
Estimates represent relative risk ratios (RRRs; and 95% confidence intervals [CIs]) from multinomial models adjusted for age, sex, race-site, education, hypertension, diabetes, body mass index, and *APOE* ε4. Referent group was cognitively normal. All estimates are from separate models for linear amyloid-β (Aβ) ratio, Aβ ratio with splines, and continuous Aβ₄₂ and Aβ₄₀ at each visit.

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Association of Midlife Plasma Amyloid-β Levels With Cognitive Impairment in Late Life: The ARIC Neurocognitive Study

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Association of Midlife Plasma Amyloid-β Levels With Cognitive Impairment in Late Life: The ARIC Neurocognitive Study

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