AIMS: To investigate midlife cholesterol in relation to Alzheimer’s disease (AD) and vascular dementia (VaD) in a large multiethnic cohort of women and men. METHODS: The Kaiser Permanente Northern California Medical Group (healthcare delivery organization) formed the database for this study. The 9,844 participants underwent detailed health evaluations during 1964-1973 at ages 40-45 years; they were still members of the health plan in 1994. AD and VaD were ascertained by medical records between 1 January 1994 and 1 June 2007. Cox proportional hazards models – adjusted for age, education, race/ethnic group, sex, midlife diabetes, hypertension, BMI and late-life stroke – were conducted. RESULTS: In total, 469 participants had AD and 127 had VaD. With desirable cholesterol levels (<200 mg/dl) as a reference, hazard ratios (HR) and 95% CI for AD were 1.23 (0.97-1.55) and 1.57 (1.23-2.01) for borderline (200-239 mg/dl) and high cholesterol (>or=240 mg/dl), respectively. HR and 95% CI for VaD were 1.50 (1.01-2.23) for borderline and 1.26 (0.82-1.96) for high cholesterol. Further analyses for AD (cholesterol quartiles, 1st quartile reference) indicated that cholesterol levels >220 mg/dl were a significant risk factor: HR were 1.31 (1.01-1.71; 3rd quartile, 221-248 mg/dl) and 1.58 (1.22-2.06; 4th quartile, 249-500 mg/dl). CONCLUSION: Midlife serum total cholesterol was associated with an increased risk of AD and VaD. Even moderately elevated cholesterol increased dementia risk. Dementia risk factors need to be addressed as early as midlife, before underlying disease(s) or symptoms appear.