Recent evidence suggests an association of beta-amyloid (Abeta) with vascular risk factors and the medications to treat them, which could potentially obfuscate the usefulness of Abeta for prediction of mild cognitive impairment (MCI) or Alzheimer disease (AD). In a subcohort from the Alzheimer's Disease Anti-inflammatory Prevention Trial (enriched for family history of AD), we investigated whether systolic blood pressure, total cholesterol, triglycerides, serum creatinine, apolipoprotein E, and use of statins and antihypertensives influenced the predictive value of serum Abeta for MCI/AD during a 2-year period. We collected blood samples to quantify serum Abeta from cognitively normal participants (n = 203) at baseline and ascertained the outcome of MCI/AD (n = 24) for a period of approximately 2 years. In an unadjusted model, the lowest quartile of Abeta(1-42) (hazard ratio [HR] = 2.93, 95% CI [1.02-8.32], P = 0.04) and of the Abeta(1-42)/Abeta(1-40) ratio (HR = 3.53, 95% CI [1.24-10.07], P = 0.02), compared with the highest quartile, predicted conversion to MCI/AD, but no impact of Abeta(1-40) was observed. No relationship between nonsteroidal antiinflammatory drug interventions and Abeta on MCI/AD risk was evident. Once data were adjusted for potential confounders (age, sex, and education), vascular risk factors, and the medications listed above, the lowest quartiles of Abeta(1-42) (HR = 4.47, 95% CI [1.39-14.39], P = 0.01), and of the Abeta(1-42/)Abeta(1-40) ratio (HR 4.87, 95% CI [1.50-15.87], P = 0.01) became strong predictors of conversion to MCI/AD. In this subcohort of individuals at risk for AD, the association of Abeta with vascular risk factors and medications to treat these conditions did not interfere with Abeta's predictive value for MCI/AD.