Objective. To evaluate the association between midlife plasma amyloid-beta (Aβ_1-42, Aβ_1-40, Aβ₄₂:Aβ₄₀) and risk of MCI and dementia.

Plasma Aβ₄₂ and Aβ₄₀ were retrospectively measured using a fluorimetric bead-based immunoassay in a subsample of the Atherosclerosis Risk in Communities study (n=2284) at the third (1993-95, mean age=59.2±5.2, 57% female, 22% Black) and fifth in-person visits (2011-13, mean age=77.0±5.3). We investigated the relationship of plasma Aβ₄₂, Aβ₄₀, and Aβ₄₂:Aβ₄₀ ratio measured in midlife, late-life, and the change from midlife to late-life, to risk of MCI, dementia, and combined MCI/dementia outcomes in late-life (from 2011-19). We used multinomial logistic regressions estimating relative risk ratios (RRR) of these cognitive outcomes vs cognitively normal adjusted for age, sex, education, site-race, APOE, hypertension, diabetes, and body mass index. Each doubling of midlife Aβ₄₂:Aβ₄₀ was associated with 37% lower risk of MCI/dementia (RRR=0.63, 95% CI: 0.46, 0.87), but only up to approximately the median (spline model threshold 0.20). Every standard deviation 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 standard deviation 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 repeating models using late-life plasma Aβ predictors. Aβ₄₂ and Aβ₄₀ increased from midlife to late-life, but changes were not associated with cognitive outcomes. Midlife measurement of plasma Aβ may have utility as a blood-based biomarker indicative of risk for future cognitive impairment.