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

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.

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.