Objectives: To examine the association between incident Alzheimer disease (AD), and plasma A1-40 and A1-42 levels in normal and mild cognitive impairment (MCI) subjects in a subgroup of participants of the Cardiovascular Health Study Cognition Study.

Methods: We determined the plasma A1-40 and A1-42 levels of 274 nondemented subjects (232 normals and 42 with MCI) in 1998–1999 and repeated the measurements in 2002–2003. The mean age of the subjects at baseline was 79.3 ± 3.6 years. We examined the association between A levels and incident AD over the ensuing 4.5 years, controlling for age, cystatin C level (marker of glomerular function), apolipoprotein E-4 allele, Modified-Mini-Mental State Examination scores, and MRI-identified infarcts.

Results: In an unadjusted prospective model in normal subjects, both A1-40 and A1-42 levels in 1998–1999 were associated with incident AD (n = 55) in 2002–2003 (longitudinal analysis). In the fully adjusted multivariate model, neither A1-42 nor A1-40 nor their ratio was associated with incident AD. However, adjustment had a very small effect on point estimates for A1-42, from an odds ratio (OR) of 1.61 (p = 0.007) in the unadjusted model to an OR of 1.46 (p = 0.08) in the fully adjusted model. In 2002–2003 (cross-sectional analysis), only the unadjusted models showed that both peptides were associated with AD.

Conclusions: Plasma A levels are affected by age and by systemic and CNS vascular risk factors. After controlling for these conditions, A-40 and A1-42 are weak predictors of conversion to Alzheimer disease (AD) in normal subjects and are only weakly associated with AD in cross-sectional analysis. Consequently, plasma levels of A do not seem to be useful biomarkers for AD.