Resveratrol for Alzheimer's Disease

This double blind, placebo-controlled trial will be conducted at approximately 26
Alzheimer's Disease Cooperative Study (ADCS) clinical centers. One hundred twenty (120)
patients with mild to moderate dementia due to probable Alzheimer's disease (AD) will be
randomly assigned to treatment (1:1) with resveratrol starting at 500 mg once daily or
matching placebo, increasing at 13 week intervals to a maximum of 1 gram twice daily
(divided into two 500 mg capsules taken orally) taken with or without food. Participants
will be treated for 52 weeks, and will undergo venous blood draws for biomarker analysis at
Baseline and at 52 weeks; participants will also undergo two lumbar punctures for biomarker
analyses of cerebrospinal fluid (CSF) at Baseline and at Week 52. Participants will undergo
magnetic resonance imaging (MRI) to measure rate of whole-brain and regional atrophy at
Screening, Week 13 and Week 52 visits. Randomization will be stratified by site. For
monitoring of potential toxicities of the study drug - particularly nephrotoxicity -
subjects will undergo physical examination, neurological examination, adverse event review,
blood chemistries to include blood urea nitrogen (BUN) and Creatinine (Cr), pharmacokinetic
(PK) analyses for resveratrol and its metabolites, and urinalysis every 6-7 weeks during the
study. Clinical, Cognitive and Functional effects of resveratrol and insulin and glucose
metabolism will also be assessed.

A subgroup of approximately 15 subjects enrolled will be randomized 4:1 (N = 15, 12 treated
+ 3 placebo) for more detailed 24-hour PK analysis. For these individuals, blood samples
will be collected at 15 different time points. Measurements will include levels of
resveratrol and its major metabolites (sulfated- and glucuronidated-resveratrol). These
subjects will complete the detailed PK with each dosage step. This 24-hour PK sampling in
the subgroup will occur after the first dose following Baseline, after the first dose at
each dose increment (Weeks 13, 26 and 39), and after the final dose (Week 52).

Enrollment will be restricted to individuals who are able to abstain from ingesting large
quantities of resveratrol-containing foods (including red wine). 1-2 glasses of red wine or
red grape juice and 1 serving of red grapes daily is acceptable. Subjects must also be able
to abstain from ingesting herbal/natural preparations or dietary supplements containing
resveratrol.

Inclusion Criteria:

- Diagnosis of probable AD (NINDS-ADRDA criteria).

- Age must be 50 years or older.

- Able to ingest oral medications.

- Caregiver/Study Partner who has direct contact with the participant more than 2 days
per week to accompany participant to all visits.

- MMSE score between 14 and 26 (inclusive).

- Modified Hachinski score of less than or equal to 4.

- Able to abstain from ingesting large quantities of resveratrol-containing foods
(including red wine). 1-2 glasses of red wine or red grape juice daily acceptable; 1
serving of red grapes daily acceptable.

- Able to abstain from ingesting herbal/natural preparations or dietary supplements
containing resveratrol.

Exclusion Criteria:

- Non-AD dementia.

- Probable AD with Down syndrome.

- History of clinically significant stroke.

- Current evidence or history in past two years of epilepsy, focal brain lesion, head
injury with loss of consciousness or DSM-IV criteria for any major psychiatric
disorder including psychosis, major depression, bipolar disorder, alcohol or
substance abuse.

- Sensory impairment that would preclude the participant from participating in or
cooperating with the protocol.

- Use of investigational agent within two months of Screening.

- Evidence of any significant clinical disorder or laboratory finding that renders the
participant unsuitable for receiving an investigational drug including clinically
significant or unstable hematologic, hepatic, cardiovascular, pulmonary,
gastrointestinal, endocrine, metabolic, renal or other systemic disease or laboratory
abnormality.

- Active neoplastic disease, history of cancer five years prior to screening, including
breast cancer (history or skin melanoma or stable prostate cancer are not excluded).

- History of seizure within past five years.

- Pregnancy or possible pregnancy.

- Use of resveratrol containing supplements.