Adults with Down syndrome (DS) are at significantly higher risk of Alzheimer's disease (AD) than the general population, but there is considerable variability in age at onset. This study tested the hypothesis that total cholesterol (TC) levels are related to vulnerability, and that the use of statins may decrease risk. The relation of TC level and statin use to risk of AD was investigated in 123 Caucasian adults with DS. Evaluations included serial assessments of cognitive, adaptive and maladaptive behavior, medical records, and neurological examinations. Mean length of follow-up was 5.5 years [1.2-7.1] for the entire sample, 5.1 years [1.2-7.1] for subjects who developed dementia, and 5.6 years [1.5-7.1] for those who did not develop dementia. Controlling for covariates, participants with TC>or=200mg/dL were more than two times as likely to develop AD than subjects with lower TC [hazard rate (HR)=2.59, p=.029, 95% CI: 1.1, 6.1]. In contrast, participants with higher TC levels who used statins during the study, had less than half the risk of developing AD than participants with higher TC levels who did not use statins (HR=.402, p=.095, 95% CI: .138, 1.173). If the protective effects of statins can be further validated, these findings suggest that their use may delay or prevent AD onset in vulnerable populations.