This application is a resubmission of a competing continuation proposal to study the effects of cholesterol-lowering medications on psychological functions. Current national health policy recommends widespread serum cholesterol reduction. However, little is known regarding the potential cognitive, affective, and behavioral sequelae of cholesterol-lowering treatments. The principal objective of the initial project was to determine whether cholesterol lowering by a common medication (lovastatin) caused alterations in behavior, cognition or mood, relative to placebo-treated controls. The results indicate that treatment with lovastatin worsens performance across a range of indices of cognitive functioning, particularly measures of attention and psychomotor speed. To determine whether these findings warrant public health concern, the cognitive sequelae of cholesterol lowering now require re-examination in the context of complex tasks representative of daily life. In a double-blind, placebo-controlled clinical investigation, 300 healthy adults with hypercholesterolemia will be randomly assigned to one of three treatment conditions -- simvastatin 5 mg per day, simvastatin 40 mg per day, and placebo -- for a period of six months. The principal objective of the proposed research is to evaluate the effects of cholesterol lowering on patients' performance on tasks that impose complex cognitive demands that are analogous to situations encountered frequently in everyday life. The components of the test battery are: 1) automobile driving (simulation), 2) everyday memory tests, 3) pre-employment aptitude and performance tests, 4) social cognition and behavior, (evaluated by standardized scenario presentation and significant other ratings), and 5) standard neuropsychological tests (for comparison with prior results). The use of two treatment intensities will permit examination of the dose-response relationship between the degree of cholesterol lowering and cognitive performance.
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