• Changes in biomarkers of CNS cholesterol metabolism, inflammatory markers, and cerebral perfusion [ Time Frame: 9 months ] [ Designated as safety issue: No ]
• Changes in cognitive function [ Time Frame: 9 months ] [ Designated as safety issue: No ]

• Changes in biomarkers of CNS cholesterol metabolism, inflammatory markers, and cerebral perfusion [ Time Frame: 9 months ]
• Changes in cognitive function [ Time Frame: 9 months ]

The purpose of this study is to see how simvastatin, a cholesterol lowering drug, affects processes related to the development of Alzheimer's disease, including: 1) levels of a substance called beta-amyloid 42 found in the fluid surrounding the brain, 2) blood flow in the brain, 3) inflammation in the brain, and 4) the brain's handling of cholesterol.

Some studies suggest that statin medications, which are a group of cholesterol-lowering medicines, may help prevent Alzheimer's disease. However, this has not been proven in humans. The purpose of this study is to see how simvastatin affects substances in the body called beta-amyloid 40 and beta-amyloid 42, as well as blood flow to the brain. These substances are found in both the brain and the fluid around the brain and spinal cord. High amounts of these substances may be associated with a greater risk of getting Alzheimer's disease.

The ESPRIT study will include 100 middle-aged adults (35-69 yrs) who have a parent with documented Alzheimer's disease. This study will see how the use of a particular statin medication, simvastatin, affects spinal fluid levels of beta-amyloid, inflammation, and cholesterol. In addition, these changes will be compared to changes in memory and thinking skills monitored throughout the study. Fifty of the ESPRIT subjects will also participate in the MRI substudy, which is examining the effects of the study medication on blood flow to structures in the brain that are associated with Alzheimer's disease.

Participants will take part in 5 visits (and an additional 2 visits, if participating in the MRI substudy) over the course of 9 months. Participants will undergo fasting blood tests (baseline, month 3, and month 9 visits), complete a medical history questionnaire (baseline), complete medication side effect review through questionnaire and/or blood sample (all visits), undergo lumbar puncture procedure (baseline and month 9 visits), complete memory testing (baseline, month 3 and month 9 visits), and MRI procedure (baseline and month 9 visits), if participating in MRI substudy. Participants will be randomly assigned to receive either simvastatin or a placebo each night for 9 months.

• Drug: Simvastatin
• Drug: Placebo

• Fassbender K, Simons M, Bergmann C, Stroick M, Lutjohann D, Keller P, Runz H, Kuhl S, Bertsch T, von Bergmann K, Hennerici M, Beyreuther K, Hartmann T. Simvastatin strongly reduces levels of Alzheimer's disease beta -amyloid peptides Abeta 42 and Abeta 40 in vitro and in vivo. Proc Natl Acad Sci U S A. 2001 May 8;98(10):5856-61. Epub 2001 Apr 10.
• Wolozin B. A fluid connection: cholesterol and Abeta. Proc Natl Acad Sci U S A. 2001 May 8;98(10):5371-3. No abstract available.
• Johnson NA, Jahng GH, Weiner MW, Miller BL, Chui HC, Jagust WJ, Gorno-Tempini ML, Schuff N. Pattern of cerebral hypoperfusion in Alzheimer disease and mild cognitive impairment measured with arterial spin-labeling MR imaging: initial experience. Radiology. 2005 Mar;234(3):851-9.

Inclusion Criteria:

• Age 35 to 69
• Parent with Alzheimer's disease

Exclusion Criteria:

• Current use of cholesterol lowering medication
• History of liver disease
• History of adverse reaction to statin medications
• History of previous lumbar spine surgery
• Elevated lab values (creatine kinase and creatinine)
• Use of prohibited medications: Simvastatin, Pravastatin, Cholestyramine, Lovastatin, Colestipol, Gemfibrozil, Niacin, Atorvastatin, Fluvastatin, Fenofibrate, Rosuvastatin, Clarithromycin, Cyclosporine, Digoxin, Erythromycin, Itraconazole, Ketaconazole, Fluconazole, Nefazodone, Warfarin, Saquinavir, Ritonavir, Indinavir, Nelfinavir, Amprenavir, Amiodarone, Verapamil
• History of dementia
• Currently pregnant
• Use of large quantities of grapefruit juice (more than 1 quart per day)
• Current involvement in another investigational drug study
• Contraindications to MRI

• Paul Beeson Faculty Scholars Program
• The John A. Hartford Foundation
• The Atlantic Philanthropies
• Starr Foundation
• American Federation for Aging Research
• Merck