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

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish (US)
Pages (from-to)E1123-E1131
Issue number11
StatePublished - Sep 14 2021

ASJC Scopus subject areas

  • Clinical Neurology


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