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A randomized, double-blind, placebo-controlled trial of resveratrol for Alzheimer disease

Raymond Scott TurnerFrom the Department of Neurology (R.S.T., B.A.R.), Georgetown University, Washington, DC; the Department of Neurosciences (R.G.T., J.B.B., R.A.R., R.R., P.S.A.), University of California, San Diego, La Jolla; the Department of Internal Medicine (S.C.), Wake Forest University, Winston-Salem, NC; the Departments of Psychiatry, Neurology, and Neurobiology (C.H.v.D.), Yale University, New Haven, CT; and the Clinical Biotechnology Research Institute (J.M.), Roper St. Francis Healthcare, Charleston, SCRonald G. ThomasFrom the Department of Neurology (R.S.T., B.A.R.), Georgetown University, Washington, DCSuzanne CraftFrom the Department of Neurology (R.S.T., B.A.R.), Georgetown University, Washington, DCChristopher H. van DyckFrom the Department of Neurology (R.S.T., B.A.R.), Georgetown University, Washington, DC; the Department of Neurosciences (R.G.T., J.B.B., R.A.R., R.R., P.S.A.), University of California, San Diego, La Jolla; the Department of Internal Medicine (S.C.), Wake Forest University, Winston-Salem, NC; the Departments of Psychiatry, Neurology, and Neurobiology (C.H.v.D.), Yale University, New Haven, CT; and the Clinical Biotechnology Research Institute (J.M.), Roper St. Francis Healthcare, Charleston, SCJacobo MintzerFrom the Department of Neurology (R.S.T., B.A.R.), Georgetown University, Washington, DCBrigid Reynoldsthe Clinical Biotechnology Research Institute (J.M.), Roper St. Francis Healthcare, Charleston, SCJames B. BrewerWake Forest UniversityRobert A. Rissmanthe Clinical Biotechnology Research Institute (J.M.), Roper St. Francis Healthcare, Charleston, SCRema Ramanthe Departments of Psychiatry, Neurology, and Neurobiology (C.H.v.D.), Yale University, New Haven, CTPaul AisenFrom the Department of Neurology (R.S.T., B.A.R.), Georgetown University, Washington, DCFor the Alzheimer's Disease Cooperative Studythe Department of Internal Medicine (S.C.), Wake Forest University, Winston-Salem, NCAlzheimer's Disease Cooperative Studythe Department of Neurosciences (R.G.T., J.B.B., R.A.R., R.R., P.S.A.), University of California, San Diego, La JollaJacobo Mintzerthe Department of Internal Medicine (S.C.), Wake Forest University, Winston-Salem, NCBrent A. Reynoldsthe Department of Neurosciences (R.G.T., J.B.B., R.A.R., R.R., P.S.A.), University of California, San Diego, La JollaJason Karlawishthe Departments of Psychiatry, Neurology, and Neurobiology (C.H.v.D.), Yale University, New Haven, CTDouglas Galaskothe Department of Neurosciences (R.G.T., J.B.B., R.A.R., R.R., P.S.A.), University of California, San Diego, La JollaJudith L. HeidebrinkFrom the Department of Neurology (R.S.T., B.A.R.), Georgetown University, Washington, DCNeel Aggarwalthe Department of Internal Medicine (S.C.), Wake Forest University, Winston-Salem, NCNeill R. Graff‐RadfordFrom the Department of Neurology (R.S.T., B.A.R.), Georgetown University, Washington, DCMary Sanothe Department of Internal Medicine (S.C.), Wake Forest University, Winston-Salem, NCRonald C. PetersenFrom the Department of Neurology (R.S.T., B.A.R.), Georgetown University, Washington, DCKatheryn A. BellRachelle S. DoodyFrom the Department of Neurology (R.S.T., B.A.R.), Georgetown University, Washington, DCAlisha J SmithCharles Bernickthe Department of Neurosciences (R.G.T., J.B.B., R.A.R., R.R., P.S.A.), University of California, San Diego, La JollaA. Porteinssonthe Departments of Psychiatry, Neurology, and Neurobiology (C.H.v.D.), Yale University, New Haven, CTPierre N. TariotRuth A. Mulnardthe Clinical Biotechnology Research Institute (J.M.), Roper St. Francis Healthcare, Charleston, SCA. Lernerthe Departments of Psychiatry, Neurology, and Neurobiology (C.H.v.D.), Yale University, New Haven, CTLuisa‐Sophie SchneiderFrom the Department of Neurology (R.S.T., B.A.R.), Georgetown University, Washington, DCJane C. Burnsthe Department of Internal Medicine (S.C.), Wake Forest University, Winston-Salem, NCMurray A. Raskindthe Departments of Psychiatry, Neurology, and Neurobiology (C.H.v.D.), Yale University, New Haven, CTSteven H. FerrisFrom the Department of Neurology (R.S.T., B.A.R.), Georgetown University, Washington, DCGregory A. JichaFrom the Department of Neurology (R.S.T., B.A.R.), Georgetown University, Washington, DCM. Quicenothe Department of Neurosciences (R.G.T., J.B.B., R.A.R., R.R., P.S.A.), University of California, San Diego, La JollaThomas O. Obisesanthe Clinical Biotechnology Research Institute (J.M.), Roper St. Francis Healthcare, Charleston, SCPaul B. Rosenbergthe Department of Internal Medicine (S.C.), Wake Forest University, Winston-Salem, NCDaniel Weintraubthe Departments of Psychiatry, Neurology, and Neurobiology (C.H.v.D.), Yale University, New Haven, CTKarl KieburtzFrom the Department of Neurology (R.S.T., B.A.R.), Georgetown University, Washington, DCBruce L. Millerthe Clinical Biotechnology Research Institute (J.M.), Roper St. Francis Healthcare, Charleston, SCRichard J. KryscioG. Alexopoulis

2015en

ABI

Annotatsiya

OBJECTIVE: A randomized, placebo-controlled, double-blind, multicenter 52-week phase 2 trial of resveratrol in individuals with mild to moderate Alzheimer disease (AD) examined its safety and tolerability and effects on biomarker (plasma Aβ40 and Aβ42, CSF Aβ40, Aβ42, tau, and phospho-tau 181) and volumetric MRI outcomes (primary outcomes) and clinical outcomes (secondary outcomes). METHODS: Participants (n = 119) were randomized to placebo or resveratrol 500 mg orally once daily (with dose escalation by 500-mg increments every 13 weeks, ending with 1,000 mg twice daily). Brain MRI and CSF collection were performed at baseline and after completion of treatment. Detailed pharmacokinetics were performed on a subset (n = 15) at baseline and weeks 13, 26, 39, and 52. RESULTS: Resveratrol and its major metabolites were measurable in plasma and CSF. The most common adverse events were nausea, diarrhea, and weight loss. CSF Aβ40 and plasma Aβ40 levels declined more in the placebo group than the resveratrol-treated group, resulting in a significant difference at week 52. Brain volume loss was increased by resveratrol treatment compared to placebo. CONCLUSIONS: Resveratrol was safe and well-tolerated. Resveratrol and its major metabolites penetrated the blood-brain barrier to have CNS effects. Further studies are required to interpret the biomarker changes associated with resveratrol treatment. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that for patients with AD resveratrol is safe, well-tolerated, and alters some AD biomarker trajectories. The study is rated Class II because more than 2 primary outcomes were designated.

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DOI: 10.1212/wnl.0000000000002035

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