Plasma Aβ1–40 and Aβ1–42 and the risk of dementia: a prospective case-cohort study

SummaryBackgroundAmyloid β peptides (Aβ) are important components of plaques in Alzheimer's disease. Plasma concentrations of Aβ1–40 and Aβ1–42 rise with age and are increased in people with mutations that cause early-onset Alzheimer's disease. However, Aβ1–42 concentrations may decrease early in the dementia process. We postulated that concentrations of Aβ1–40 and Aβ1–42 in plasma are associated with risk of dementia.MethodsWe did a case-cohort study embedded in the prospective, population-based Rotterdam Study. Of 6713 participants at risk for dementia, a random sample of 1756 people was drawn. During follow-up (mean 8·6 years), 392 incident dementia cases were identified. We investigated the association between plasma Aβ concentrations and risk of dementia and its subtypes using Cox proportional hazard models.FindingsHigh concentrations of Aβ1–40 but not Aβ1–42 at baseline were associated with an increased risk of dementia. Compared with the first quartile of Aβ1–40, age and sex-adjusted hazard ratios for dementia for the second, third, and fourth quartiles were 1·07 (95% CI 0·72–1·58), 1·16 (0·78–1·70), and 1·46 (1·01–2·12). People with an increased Aβ1–42/Aβ1–40 ratio had a reduced risk of dementia. Compared with the first quartile of the Aβ1–42/Aβ1–40 ratio, hazard ratios for the second, third, and fourth quartiles were 0·74 (0·53–1·02), 0·62 (0·44–0·88), and 0·47 (0·33–0·67). Associations were similar for Alzheimer's disease and vascular dementia.InterpretationHigh plasma concentrations of Aβ1–40, especially when combined with low concentrations of Aβ1–42, indicate an increased risk of dementia. A potential role of plasma Aβ concentrations as a marker of incipient dementia warrants further investigation.