Medical Research: What is the background for this study? What are the main findings?
Dr. Turner: The resveratrol trial originated from the extensive scientific literature demonstrating that caloric restriction (consuming only 2/3 usual calories) prevents or delays diseases of aging – including Alzheimer’s disease (AD) in laboratory animals. The molecular mechanism is thought to involve sirtuins – a group of genes/proteins that sense energy balance to regulate gene expression. Sirtuins are activated by caloric restriction (a mild stressor) to express genes that promote resilience of the organism. Resveratrol is a potent activator of sirtuins – thus bypassing the requirement for caloric restriction. On the opposite side of the coin – caloric excess, midlife obesity, and diabetes are strong risk factors for Alzheimer’s disease. And we have long-known that resveratrol is found in red grapes, red wine, and other foods that promote general health.
Medical Research: What are the main findings? What should clinicians and patients take away from your report?
Dr. Turner: The study was a randomized, double-blind, placebo-controlled Phase 2 trial – that proved that high doses of pterostilbene resveratrol supplements (up to 1000 mg by mouth twice daily) are safe in patients with mild to moderate Alzheimer’s disease treated for 12 months. Despite extensive metabolism, we proved that a small fraction of resveratrol penetrates the blood brain barrier. We found that some Alzheimer’s disease biomarkers are altered by resveratrol – for example, treatment blocked the depletion of amyloid proteins in blood and cerebrospinal fluid as they deposit in the brain to cause neurotoxicity and progressive dementia. Resveratrol treatment increased brain shrinkage compared to the placebo group, perhaps due to its anti-inflammatory effect and decreased brain swelling (this has been reported with other proposed AD treatments). The major side effect of resveratrol was weight loss (~ 1 kg over 12 months). There were more cancers in the placebo-treated group than the resveratrol-treated group (since aging is a major risk factor for cancer, resveratrol is also being studied for cancer prevention). We did not expect to find cognitive effects of treatment (due to the small sample size of 119 patients in total), but the resveratrol-treated group declined less in activities of daily living (using a telephone, preparing meals, etc.).
Medical Research: What recommendations do you have for future research as a result of this study?
Dr. Turner: We used pure synthetic resveratrol. The supplements on the market are not regulated and cannot be recommended without further study. We are now analyzing samples from the completed study to examine mechanism of action, and preparing a larger Phase 3 trial to test the efficacy of resveratrol treatment on cognition in patients with mild AD. More potent and bioavailable sirtuin activating compounds (STACs) are also being developed by industry. This study opens the door to a potential new strategy for AD treatment that does not focus on amyloid directly, and may be useful for the prevention or treatment of all diseases of aging.
S. Turner, R. G. Thomas, S. Craft, C. H. van Dyck, J. Mintzer, B. A. Reynolds, J. B. Brewer, R. A. Rissman, R. Raman, P. S. Aisen. A randomized, double-blind, placebo-controlled trial of resveratrol for Alzheimer disease. Neurology, 2015; DOI:10.1212/WNL.0000000000002035
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R. Scott Turner, MD, PhD (2015). Can High-Dose Resveratrol Slow Dementia?