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

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 Ab40 and Ab42, CSF Ab40, Ab42, tau, and phospho-tau 181) and volumetric MRI outcomes (primary outcomes) and clinical outcomes (secondary outcomes). Methods: Participants (n 5 119) 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 5 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 Ab40 and plasma Ab40 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. Neurology® 2015;85:1–9 GLOSSARY 3G-RES 5 3-O-glucuronidated-resveratrol; 4G-RES 5 4-O-glucuronidated-resveratrol; AD 5 Alzheimer disease; ADAScog 5 Alzheimer’s Disease Assessment Scale–cognitive; ADCS 5 Alzheimer’s Disease Cooperative Study; ADCS-ADL 5 Alzheimer’s Disease Cooperative Study Activities of Daily Living Scale; AE 5 adverse event; BMI 5 body mass index; CDRSOB 5 Clinical Dementia Rating-sum of boxes; Cmax 5 maximal plasma concentration; DMSO 5 dimethyl sulfoxide; ITT 5 intention-to-treat; MMRM 5 mixed-model repeated-measures; MMSE 5 Mini-Mental State Examination; NPI 5 Neuropsychiatric Inventory; S-RES 5 3-sulfated-resveratrol; SAE 5 serious adverse event.