An association between plasma Amyloid beta peptides (Aβ) with blood lipids was reported in cross-sectional studies. The present study examined the 5-year prospective association of atherosclerotic risk factors with plasma Aβ42 in 440 elderly persons without both Alzheimer's disease (AD) or mild cognitive impairment (MCI) at baseline. Persons in the highest tertile of total cholesterol (TC) or LDL-C at baseline showed low plasma Aβ42 at 5 years. Regression analysis confirmed TC and LDL-C as negative predictors of Aβ42 (p = 0.001). An increase over 5 years of HDL-C was a negative predictor and the presence of an APOE ε4 allele was a positive predictor for decrease of Aβ42 in converters to MCI. In converters to AD, increase of both TC and of HbA1c were positive predictors of Aβ42 levels at 5 years. Analysis of covariance showed a positive association between Δ-TC, Δ-LDL-C, Δ-HbA1c, and levels of Aβ42 at 5 years (p = 0.006; 0.013 and 0.027 resp.) in converters to AD independently on lipid-lowering treatment. The association of vascular risk factors TC, LDL-C, and HbA1c with higher Aβ42 levels might, after confirmation in other cohorts, influence the development of lifestyle interventions concerning plasma Aβ42 and AD.