To study the relationship between plasma levels of amyloid beta (Abeta) peptides and dementia in aging individuals with Down syndrome, we investigated the relationship among plasma Abeta, apolipoprotein E genotype and cognitive and clinical factors using baseline specimens form participants in an ongoing clinical trial in individuals with Down syndrome 50 years of age and older. Because of substantial skew in the distribution of peptide levels, analyses used log transformations of the data. The ratio of Abeta42 to Abeta40 was associated with the presence of dementia (P=0.003, df=196, F=9.37); this association persisted after adjustment for age, sex level of mental retardation, and apolipoprotein E genotype. Consistent with recent reports regarding the effect of presenilin mutations on peptide generation, our finding supports the theory that the ratio of Abeta42 to Abeta40 rather than absolute levels of the peptides is important to the pathophysiology of Alzheimer's disease in genetically susceptible populations.