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

Background: Amyloid 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. Methods: We 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. Findings: High 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. Interpretation: High 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.

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