Results from the largest nationwide study investigating long-term high-dose resveratrol in patients with mild to moderate Alzheimer’s disease (AD) showed that a specific a biomarker that declines with disease progression was stabilized in patients who received resveratrol in its purified form.
The results, published online in Neurology, “are very interesting,” according to the study’s principal investigator, R. Scott Turner, MD, PhD, director of the Memory Disorders Program at Georgetown University Medical Center (pictured). Turner, who treats patients at MedStar Georgetown University Hospital, cautions that the findings cannot be used to recommend resveratrol. “This is a single, small study with findings that call for further research to interpret properly.”
Resveratrol is found in dark chocolate, raspberries, red grapes, as well as in some red wines. Since pure synthetic (pharmaceutical-grade) resveratrol is not available commercially, the team of researchers required an “investigational new drug” application by the U.S. Food and Drug Administration.
The study was a Phase II, randomized, double-blind, placebo-controlled, clinical trial in patients with mild to moderate dementia due to AD. A total of 119 patients were enrolled in the 12 months trial and the highest dose of resveratrol evaluated was one gram given orally twice per day.
Results showed that those patients who received increasing doses of resveratrol had slight to no changes in amyloid-beta40 (Abeta40) levels in their cerebrospinal fluid and blood, in contrast to patients who were treated with the placebo, who had a decrease in the levels of Abeta40.
“A decrease in Abeta40 is seen as dementia worsens and Alzheimer’s disease progresses; still, we can’t conclude from this study that the effects of resveratrol treatment are beneficial,” Turner explained. “It does appear that resveratrol was able to penetrate the blood brain barrier, which is an important observation. Resveratrol was measured in both blood and cerebrospinal fluid.”
John Bozza, aged 80 years, took part in the study. About five years ago, Diana, his wife, started to realize that “something wasn’t quite right.” He got a diagnosis of mild cognitive impairment and one year after he fully developed mild Alzheimer’s Disease. Diana, who had seen her twin sister die from the same condition said there are many reasons why she and John have decided to take part in the study. Now they are aware that John was in the active drug group.
“I definitely want the medical community to find a cure,” she said. “And of course I thought there’s always a chance that John could have been helped, and who knows, maybe he was.”
The team decided to investigate resveratrol since the drug activates specific proteins known as sirtuins, which are also activated by restriction to calories. Aging is the biggest risk factor for AD, with results from animal studies showing that most diseases related with aging can be delayed or prevented by caloric restriction.
According to Turner, results from the study showed that resveratrol was well tolerated and safe. The most common side effects observed were nausea and diarrhea. Moreover, compared to placebo participants, those receiving resveratrol lost weight.
Turner noted that one result was particularly confounding: brain MRI scans, prior and following the study, showed that patients who were treated with resveratrol had an increased brain volume loss compared to the placebo group . “We’re not sure how to interpret this finding. A similar decrease in brain volume was found with some anti-amyloid immunotherapy trials,” Turner added. A working hypothesis is that the treatment may reduce inflammation (or brain swelling) found in Alzheimer’s patients.
Studies are being conducted to test possible drug mechanisms, including an analysis of frozen blood and cerebrospinal fluid taken from patients. “Given safety and positive trends toward effectiveness in this phase 2 study, a larger phase 3 study is warranted to test whether resveratrol is effective for individuals with Alzheimer’s — or at risk for Alzheimer’s,” Turner said.
Resveratrol and other similar drug agents are currently being investigated in many age-related diseases such as diabetes, cancer, and neurodegenerative conditions. However, this new study is, to date, the longest, largest, and highest dose clinical trial of resveratrol in humans.