Therapy Type: Small Molecule (timeline), Dietary Supplement (timeline)
Target Type: Other (timeline)
Condition(s): Alzheimer's Disease, Mild Cognitive Impairment
U.S. FDA Status: Alzheimer's Disease (Phase 3), Mild Cognitive Impairment (Phase 4)
Resveratrol is one of many bioactive polyphenols in certain foods, such as red grapes, blueberries, peanuts, and dark chocolate. It has been reported to have neuroprotective effects in cell-based and animal models. These were attributed to resveratrol's antioxidant capacity, or to specific processes such as prevention of amyloid deposition (Karuppagounder et al., 2009) or induction of the sirtuin 1 gene to increase translation of the anti-aging enzyme sirtuin (Kim et al., 2007). Besides Alzheimer's disease, resveratrol has been studied for the treatment of cardiovascular and metabolic disease, cancers, as well as pain, inflammation, and other conditions of aging (Albani et al., 2010; Li et al., 2012).
Resveratrol is available as part of a healthy diet or in the form of dietary supplements. Epidemiological research has questioned whether the dose achievable through diet has specific health benefits in aging (see May 2014 news). Resveratrol supplementation achieves higher blood levels, but resveratrol's low brain penetrance may limit its potential to treat Alzheimer's disease. Clinical studies of resveratrol supplementation continue across a range of indications, while proprietary small-molecule derivatives with favorable pharmacokinetic properties are being developed, as well.
Between 2008 and 2010, a Phase 3 trial at the Veterans Affairs Medical Center in the Bronx, New York, evaluated a one-year course of treatment with a liquid formulation of resveratrol, glucose, and malate in 27 patients with mild to moderate Alzheimer's. The primary outcome was change on the ADAS-cog. This study is not yet published.
In 2010, a study at the Charite University Medical Center in Berlin began a Phase 4 study in 330 people with mild cognitive impairment (MCI). This trial evaluates resveratrol supplementation as one of six different interventions against ADAS-cog as the primary outcome and brain imaging and plasma biomarkers as secondary outcomes. This trial is set to run through 2014.
In 2013 and 2014, the Alzheimer's Disease Cooperative Study conducted a 26-center Phase 2 study across the United States to evaluate a one-year course of treatment with up to 2 grams of resveratrol capsule supplementation per day in 119 people with mild to moderate Alzheimer's. Primary outcomes were change in CSF Aβ and tau biomarkers, safety and tolerability, and change in brain and hippocampal volume as measured by MRI. This trial includes a pharmacokinetic substudy that will measure resveratrol levels over a 24-hour period in 15 participants. At CTAD 2014, and in a peer-reviewed paper later on, this trial was reported to have shown that about 1 percent of resveratrol reaches the CSF. Both plasma and CSF Aβ40 levels decreased more in the placebo than the treatment group, whereas brain atrophy was reportedly greater in the treatment versus placebo group (see discussion in Dec 2014 conference news; Turner et al., 2015).
In 2014, a small study of 46 cognitively healthy, overweight people reported that a six-month course of 200 mg of resveratrol per day taken as a supplement improved both word recall and two brain imaging measures (see Jun 2014 news).
In June 2015, a Phase 1 trial at Johns Hopkins University began evaluating three doses of a nutraceutical preparation containing resveratrol and other polyphenols in 48 prediabetic people with amnestic MCI.
Other small clinical studies have investigated the effect of resveratrol supplementation on cerebral blood flow in healthy adults, on the neurodegenerative disease Friedreich's ataxia, and on aging outcomes such as walking and cognition. For more clinical trials on resveratrol, see clinicaltrials.gov.
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- Turner RS, Thomas RG, Craft S, van Dyck CH, Mintzer J, Reynolds BA, Brewer JB, Rissman RA, Raman R, Aisen PS, Alzheimer's Disease Cooperative Study. A randomized, double-blind, placebo-controlled trial of resveratrol for Alzheimer disease. Neurology. 2015 Oct 20;85(16):1383-91. Epub 2015 Sep 11 PubMed.
- Karuppagounder SS, Pinto JT, Xu H, Chen HL, Beal MF, Gibson GE. Dietary supplementation with resveratrol reduces plaque pathology in a transgenic model of Alzheimer's disease. Neurochem Int. 2009 Feb;54(2):111-8. PubMed.
- Kim D, Nguyen MD, Dobbin MM, Fischer A, Sananbenesi F, Rodgers JT, Delalle I, Baur JA, Sui G, Armour SM, Puigserver P, Sinclair DA, Tsai LH. SIRT1 deacetylase protects against neurodegeneration in models for Alzheimer's disease and amyotrophic lateral sclerosis. EMBO J. 2007 Jul 11;26(13):3169-79. PubMed.
- Albani D, Polito L, Forloni G. Sirtuins as novel targets for Alzheimer's disease and other neurodegenerative disorders: experimental and genetic evidence. J Alzheimers Dis. 2010;19(1):11-26. PubMed.
- Li F, Gong Q, Dong H, Shi J. Resveratrol, a neuroprotective supplement for Alzheimer's disease. Curr Pharm Des. 2012;18(1):27-33. PubMed.
- Patel KR, Scott E, Brown VA, Gescher AJ, Steward WP, Brown K. Clinical trials of resveratrol. Ann N Y Acad Sci. 2011 Jan;1215:161-9. PubMed.
- Vang O, Ahmad N, Baile CA, Baur JA, Brown K, Csiszar A, Das DK, Delmas D, Gottfried C, Lin HY, Ma QY, Mukhopadhyay P, Nalini N, Pezzuto JM, Richard T, Shukla Y, Surh YJ, Szekeres T, Szkudelski T, Walle T, Wu JM. What is new for an old molecule? Systematic review and recommendations on the use of resveratrol. PLoS One. 2011;6(6):e19881. Epub 2011 Jun 16 PubMed.