Effects of Simvastatin on Biomarkers

The purpose of this study is to see if a drug called simvastatin (brand name Zocor)
beneficially affects the level of certain molecules (such as proteins) in the spinal fluid
of people. The molecules the investigators are measuring are thought to be important in the
development of Alzheimer's disease (AD), and the investigators are testing whether
simvastatin can change proteins to a level that is associated with a reduced risk for AD.

Simvastatin has been approved by the United States Food and Drug Administration (FDA) for
the treatment of high cholesterol and to reduce the risk of coronary artery disease. It is
an investigational drug in this study.

Participants will be randomly assigned to Placebo or Simvastatin. The investigators and the
participant will be blinded. Randomization will be stratified by age and gender.

This study is being funded by the National Institute on Aging. The investigators expect
about 120 people will take part in this study at the VA Puget Sound Health Care System over
the course of a 2 year enrollment period.

This study will last up to 1 year. Participants will be asked to come to the VA in Seattle a
total of 9 times, 2 of those times will be for lumbar punctures (also known as a spinal
tap).

The investigators would also like to ask a person who knows the participant well (such as a
spouse, child, sibling, or good friend) some questions about the participant's health,
memory, mood and behavior, and abilities to do daily tasks at the beginning and the end of
the study.

Participants must be cognitively normal, healthy, willing to have a lumbar puncture, and not
need or take any medications to control cholesterol.

Inclusion Criteria (participants must meet the following criteria)

- If female of childbearing potential, must have negative pregnancy test at baseline,
and all subsequent visits.

- Age 45 to 64 years inclusive.

- Considered cognitively normal with no evidence of memory or other cognitive
impairments (MMSE >26, Logical Memory delayed recall > 6, CDR score of 0).

- Normal or only mildly elevated cholesterol which does not require drug therapy based
on National Cholesterol Education Program Adult Treatment Panel III (NCEP/ATP-III)
guidelines.

- An LDL level above 70mg/dL.

- Hamilton Depression Scale (HAM-D) score < 12.

- BMI between 18 - 34 (or exception made by MD).

- In good recent general health (i.e., no trauma or infection in the 4 weeks before
LP).

- On stable dose of non-exclusionary medications for the 4 weeks preceding the LP.

- Platelet count >100,000.

Exclusion Criteria (participants must NOT satisfy any of the following conditions)

- Any contraindications to LP, such as spinal deformity, severe disease or infection in
the LP region, bleeding tendency, anticoagulant or blood-thinning medications.

- Taken a statin medication in the past 12 months.

- Any clinically significant laboratory abnormalities.

- Any neurological disorders: multiple sclerosis, epilepsy, stroke, Parkinson's, other
degenerative CNS disorders, or neuropathy with radicular involvement.

- Acute or chronic major psychiatric disorders: schizophrenia, affective disorders, or
severe anxiety disorders. (Dysthymia allowed, history of MDD allowed if currently in
remission)

- Unstable or poorly controlled medical problems such as: heart failure, diabetes
(poorly controlled or insulin dependent), hypertension (BP >160/100), pulmonary
disease with hypoxia or hypercapnia, significant liver disease or known hepatitis C
seropositivity, renal failure, treatment for cancer in the past 2 years (other than
non-melanoma skin cancer) or known HIV positive status.

- Use of illegal drugs or alcohol abuse (>2 drinks/day or 10/week) within the past
year.

- Concurrent participation in another investigational drug study.

- Use of any exclusionary medications in the 4 weeks prior to screening:

- Drugs which could interact with statins: itraconazole, ketoconazole,
erythromycin, clarithromycin, HIV protease inhibitors, nefazodone, amiodarone,
cyclosporine, isoniazid, quinidine, or large quantities of grapefruit juice (>1
quart daily)

- Central nervous system acting medications: antipsychotics, anti-Parkinson's
disease medications, anti convulsants, or CNS stimulants

- Chronic use of benzodiazepines, sedating antihistamines, or other
sedative-hypnotic agents (prn use is allowed as long as it is not within 72
hours of LP or cognitive testing)

- Medications affecting coagulation and/or inflammation: coumadin, potent
anti-inflammatory medications (hydrocortisone, methotrexate or other potent
immune-modulating medications), and anti-HIV medications (Aspirin up to 325
mg/day is allowed.)

- Lipid-lowering drugs: fibrates or niacin >500mg/day (stable dose of omega-3 is
allowed)

- Does the subject's family history meet any of the following criteria?

- Both parents had/have dementia

- On one side of the family, over two consecutive generations three relatives
had/have dementia?

- One parent had an onset of dementia before age 60?

- Does the subject have a major active autoimmune or immunological disorder?