We compared levels of plasma amyloid β-peptides Aβ1–42 and Aβ1–40 in 108 demented and nondemented adults with Down syndrome (DS) and 64 adults from the general population. Aβ1–42 and Aβ1–40 levels were significantly higher in adults with DS than in controls (P=0.0001). Compared to nondemented adults with DS, Aβ1–42 levels in demented adults with DS were selectively increased by 26% (28.2 pg/ml vs. 22.4 pg/ml, P=0.004). In addition, mean plasma levels of Aβ1–42 were 22% higher in DS cases with the apolipoprotein ε4 allele than in DS subjects without an ε4 allele (25.9 pg/ml vs. 21.2 pg/ml, P=0.01), while mean plasma levels of Aβ1–40 did not vary by APOE genotype. These results support the hypothesis that Aβ1–42 plays an important role in the pathogenesis of dementia associated with DS, as it does in Alzheimer's disease, and that variations in plasma levels may be related to disease progression.