Resveratrol is safe and well-tolerated in individuals with mild-moderate dementia due to Alzheimer’s disease. (S33.009)

Objective. A phase 2 randomized, placebo-controlled, double-blind, multicenter 12-month trial of resveratrol in individuals with mild-moderate AD. We examined safety and tolerability, and change in volumetric MRI, plasma Aβ40 and Aβ42, and CSF Aβ40, Aβ42, tau, and phosphoTau181, and clinical outcomes. Background. Similar to caloric restriction, resveratrol treatment reduces cognitive decline and neuropathology in animal models of AD - perhaps via activation of sirtuins and promotion of autophagy. Methods. Subjects (N=119) were randomized (1:1) to placebo or resveratrol 500 mg by mouth once daily (dose escalation by 500 mg every 13 weeks, ending with 1000 mg twice daily). A total of 104 subjects completed the study (12.6[percnt] dropout). Brain MRIs and CSF collections were performed at baseline and week 52. After randomization there were no differences between groups (including AD severity) with the exception of a longer disease duration in the placebo group compared to the treatment group (5.5 +/- 2.6 versus 3.9 +/- 2.3 years, mean +/- SD, p < 0.001). The primary efficacy analyses were based on intent to treat. Results. Gastrointestinal symptoms were the most common drug-related adverse events. Resveratrol and its major metabolites were measurable in plasma and CSF (with 3[percnt] BBB penetration of native resveratrol). CSF Aβ40 levels declined 14[percnt] in the placebo group and 1[percnt] in the resveratrol group, resulting in a significant difference in mean change at week 52 (p = 0.002). A similar pattern was found with plasma Aβ40 (p = 0.024). No significant differences were found with CSF and plasma Aβ42, and CSF tau and phosphoTau181. Brain volume declined 3[percnt] in the treatment group and 1[percnt] in the placebo group (p = 0.03). Conclusions. Resveratrol is safe and well-tolerated in individuals with mild-moderate AD. Further studies are needed to interpret these biomarker changes. (NIA U01 AG010483; ClinicalTrials.gov NCT01504854; FDA IND 104205). Disclosure: Dr. Turner has received personal compensation for activities with Pfizer Inc., Wyeth Pharmaceuticals, Janssen Pharmaceutica, Eli Lilly & Company, Baxter, and Ceregene as a consultant. Dr. Thomas has received personal compensation for activities with Medivation and Myriad Genetics. Dr. Craft has nothing to disclose. Dr. van Dyck has received personal compensation for activities with Yale University School of Medicine as employee. Dr. van Dyck has received personal compensation for activities with Pfizer Inc., Novartis, Janssen Pharmaceutica, and Forest Laboratories a Dr. Mintzer has nothing to disclose. Dr. Reynolds has nothing to disclose. Dr. Brewer has received personal compensation for activities with Eli Lilly & Company. Dr. Brewer holds stock and/or stock options in CorTechs Laboratories. Dr. Brewer has received research support from Janssen. Dr. Rissman has nothing to disclose. Dr. Raman has nothing to disclose. Dr. Aisen has received personal compensation for activities with Neurochem, Pfizer, Merck, Roche, Amgen, Medivation, Pamlab, Adlyfe, Eisai, GlaxoSmithKline, Eli Lilly, Daiichi, Elan, Wyeth, Avid, Novartis, and Martek as a consultant.