Context: Variants in the clusterin gene are associated with the risk of Alzheimer disease (AD) and clusterin levels have been found to be increased in brain and cerebrospinal fluid of patients with AD. Plasma clusterin was reported to be associated with brain atrophy, baseline disease severity, and rapid clinical progression in patients with AD. Objective: To evaluate the potential of plasma clusterin as a biomarker of the presence, severity, and risk of AD. Design, Setting, and Participants: A case-cohort study nested within the Rotterdam Study, a prospective population-based cohort study conducted in Rotterdam, the Netherlands. Plasma levels of clusterin were measured at baseline (1997-1999) in 60 individuals with prevalent AD, a random subcohort of 926 participants, and an additional 156 participants diagnosed with AD during follow-up until January 1, 2007 (mean [SD], 7.2 [2.3] years). Main Outcome Measures: Prevalent AD, severity of AD measured by the Mini-Mental State Examination (MMSE) score, and the risk of developing AD during follow-up. Results: The likelihood of prevalent AD increased with increasing plasma levels of clusterin (odds ratio [OR] per SD increase of plasma clusterin level, 1.63; 95% confidence interval [CI], 1.21-2.20; adjusted for age, sex, education level, apolipoprotein E status, diabetes, smoking, coronary heart disease, and hypertension). Among patients with AD, higher clusterin levels were associated with more severe disease (adjusted difference in MMSE score per SD increase in clusterin levels, -1.36; 95% CI, -2.70 to -0.02; P=.047). Plasma clusterin levels were not related to the risk of incident AD during total follow-up (adjusted HR, 1.00; 95% CI, 0.85-1.17; P for trend=.77) or within 3 years of baseline (adjusted HR, 1.09; 95% CI, 0.84-1.42; P for trend=.65). Conclusion: Plasma clusterin levels were significantly associated with baseline prevalence and severity of AD, but not with incidence of AD.