Plasma Abeta(1-40) and Abeta(1-42) and the risk of dementia: a prospective case-cohort study

Abstract

Background: Amyloid beta peptides (Abeta) are important components of plaques in Alzheimer's disease. Plasma concentrations of Abeta(1-40) and Abeta(1-42) rise with age and are increased in people with mutations that cause early-onset Alzheimer's disease. However, Abeta(1-42) concentrations may decrease early in the dementia process. We postulated that concentrations of Abeta(1-40) and Abeta(1-42) 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 Abeta concentrations and risk of dementia and its subtypes using Cox proportional hazard models.

Findings: High concentrations of Abeta(1-40) but not Abeta(1-42) at baseline were associated with an increased risk of dementia. Compared with the first quartile of Abeta(1-40), 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 Abeta(1-42)/Abeta(1-40) ratio had a reduced risk of dementia. Compared with the first quartile of the Abeta(1-42)/Abeta(1-40) 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 Abeta(1-40), especially when combined with low concentrations of Abeta(1-42), indicate an increased risk of dementia. A potential role of plasma Abeta concentrations as a marker of incipient dementia warrants further investigation.