Reviewed: Vellas B, Coley N, Ousset PJ, et al. Long-term use of standardized Ginkgo biloba extract for the prevention of Alzheimer’s disease (GuidAge): a randomized placebo-controlled trial. The Lancet Neurology. 2012;11(10):851-859.
Alzheimer’s disease (AD) is the sixth leading cause of death in the United States and is the most common form of dementia in older adults.1 The National Institute on Aging estimates that as many as 5.1 million Americans currently have AD, and experts predict the prevalence of the disease will quadruple by 2050.2,3 In September 2012, a group of French scientists published the final results of a long-term, placebo-controlled clinical trial assessing the effects of a standardized ginkgo (Ginkgo biloba, Ginkgoaceae) extract for the prevention of Alzheimer’s disease in older, healthy adults.
The GuidAge study, as it is known, was one of the largest and longest trials on Ginkgo biloba and AD prevention to date, and is the first of its kind to be performed outside the United States. Researchers found that the standardized Ginkgo biloba extract did not reduce the participants’ risk of developing Alzheimer’s disease, and some major media outlets erroneously reported that there is no benefit to taking the supplement, failing to take into account several shortcomings of the study.3
“After the results of GuidAge were published, some comments pointed out that this study provides further proof that ginkgo is ineffective in treatment of dementia. Those people are probably confusing prevention and treatment,” said Wolfgang Weber, PhD, a pharmacist with Dr. Willmar Schwabe GmbH & Co. in Karlsruhe, Germany, which developed the EGb 761® ginkgo extract used in the trial (email, October 19, 2012). Notably, EGb 761 is marketed in many countries around the world for the treatment of dementia symptoms.
“The GuidAge trial was an Alzheimer’s dementia prevention trial; EGb 761 is approved for treatment of dementia. This is definitely not comparable,” said Dr. Weber. “Today there is no compound which has an effect in prevention of AD, though there are many trials available in which different compounds (acetylcholinesterase inhibitors [AChE-I, e.g., donepezil], vitamins, statins, [nonsteroidal anti-inflammatory drugs, etc.]) were tested for that purpose. All of them failed.”
Ginkgo biloba and Alzheimer’s Disease
Alzheimer’s disease is a progressive brain disease that affects behavior and personality in addition to cognitive processes such as thinking, judgment, and memory. The exact cause of the disease is not known, but it is thought to involve buildup in the brain of certain protein fragments known as beta-almyloid (βA), which can form clumps or plaques that disrupt normal brain function and cause cell death.4
Among the primary active ingredients in ginkgo are specific flavone glycosides (e.g., rutin, quercetin, kaempferol) and unique terpene lactones (ginkgolides, bilobalides), which contribute to the neuroprotective and antioxidant properties of the extract. In animal models, the extract or components of it have been shown to increase neurogenesis and enhance neuroplasticity.5,6 Furthermore, it can inhibit βA aggregation7 and βA-induced pathological behavior.8 EGb 761, which has been used in numerous clinical trials including the 2008 US-based Ginkgo for the Evaluation of Memory (GEM) study, is standardized to 24% ginkgo flavone glycosides and 6% terpene lactones.9
In a guest comment published in the same issue of The Lancet Neurology as the recent GuidAge trial results, Lon S. Schneider, MD, director of the University of Southern California’s (USC) Alzheimer’s Disease Research and Clinical Center, wrote that EGb 761 “had a typical preclinical pharmacological profile for a modern Alzheimer’s disease drug.”10
Despite the promising pharmacological profile of ginkgo extract, the findings of the GuidAge trial were not as robust as expected. Researchers initially enrolled 2,854 healthy individuals who had reported memory problems to their primary care physicians. According to the study’s authors, “Subjective memory complaints in elderly individuals, especially if spontaneously expressed to a doctor, are associated with an increased risk of dementia, and have been linked to brain atrophy and amyloid-β deposition … and could thus be a target population for interventions aimed at prevention of Alzheimer’s disease.” After five years, 61 of the 1,406 individuals taking 240 mg ginkgo extract daily and 73 of the 1,414 participants taking a placebo equal in taste and appearance had been diagnosed with probable Alzheimer’s disease — a statistically insignificant difference.3
Potential Issues with the GuidAge Trial
In Schwabe’s “Facts and Interpretations” sheet for the GuidAge trial sent to the American Botanical Council, the company’s scientific team noted that choosing an appropriate study population for such large-scale prevention trials is problematic in itself. “Finding representative probands [i.e., study subjects with relevant genetic backgrounds] for an Alzheimer’s prevention study is extremely challenging. Even with today’s technical possibilities in analyzing genetic information, it is practically impossible to predict the probability of Alzheimer’s disease developing in a healthy individual within a defined period of time. This is also true for people already complaining about memory impairment.”
Jerry Cott, PhD — a pharmacologist and toxicologist at the US Food and Drug Administration’s Center for Drug Evaluation and Research, chair of the Center’s Dietary Supplement Subcommittee, and an ABC advisory board member — speaking on behalf of himself, acknowledged the importance of positive preclinical data for Ginkgo biloba extracts, but said he was not surprised by the results of the trial.
“The reason why this is important is that the preclinical data would suggest that there might be a preventative effect with ginkgo,” said Dr. Cott (oral communication, November 5, 2012). “This is very different from the data on cholinesterase inhibitors, which are for treating symptoms. You’re boosting the effect of what little acetylcholine is left, but you wouldn’t expect that to have a neuroprotective effect. While it’s disappointing, it’s not surprising that a preventative effect was not found in this study. No preventative effect has ever been shown for [an Alzheimer’s] treatment, including the best-selling pharmaceuticals.”
Importantly, the expected rate of AD development in the GuidAge trial — a number that must be reached to ensure ideal statistical significance — was not met. Although researchers expected the cumulative incidence rate of AD to be 13.8%, only 4.8% of trial participants were diagnosed with AD by the end of the study. According to the trial authors, the “main limitation of [the] study was that the number of dementia events was much lower than expected, leading to a lack of statistical power to detect effects.”
However, of 13 planned subgroup analyses, three groups showed a significant reduction in progression to AD: participants who stayed in the trial for at least four years, men, and those who consumed alcohol.3
According to Schwabe’s “Facts and Interpretations” document, participants in the group that took the supplement for at least four years had a 47% reduced incidence rate of AD compared to placebo. “During the first four years of treatment, the difference between EGb 761 and placebo was not significant. However, after four years, the incidence of AD for the placebo group (3.01) almost doubled compared to the rates observed in the EGb 761 group (1.51),” wrote the Schwabe scientists. “Even though the authors recommended treating these results with caution, this is a clear trend towards a possible preventative effect of EGb 761.”
USC’s Dr. Schneider, in his guest comment, offered a different explanation for the particular subgroups’ positive analysis. “The hypothesis that an individual has to take Ginkgo biloba for 4 years before it can protect against Alzheimer’s disease is essentially a proposition for a filtering or survival effect according to which — assuming participants are able to comply or survive with four years of Ginkgo biloba use and avoid discontinuing it, becoming lost to follow-up, becoming ill, becoming demented, or dying (30% of the trial participants had any of these events) — continued use into a fifth year will decrease risk for dementia,” he wrote.10
Keith Laws, PhD, a professor of cognitive neuropsychology at the University of Hertfordshire in the United Kingdom and author of a September 2012 meta-analysis of randomized, controlled clinical trials examining the effects of ginkgo on cognitive enhancement in healthy individuals, failed to detect any significant benefits in measures of memory, executive function, or attention. The 28 studies included in the analysis —which ranged in duration from five days to four months — included only individuals without dementia.11
According to Dr. Cott, making any strong conclusions from meta-analyses can be problematic. “A meta-analysis can show anything you want to show. Junk in, junk out,” he said. “The bias of the investigator can really be present in a meta-analysis.”
Dr. Laws, though, said he was impressed by the quality of the studies included in his meta-analysis. “Any meta-analysis is limited by the studies that are published, i.e., the number and quality of studies,” he said (email, October 19, 2012). “We found really high-quality studies — all were randomized, controlled trials with double blinding.”
The GuidAge study, according to Dr. Laws, also was well-crafted. “The Vellas et al. study seems very sound — it … quite clearly found Ginkgo biloba made no difference to rates of transition to Alzheimer’s,” he said (email, October 19, 2012). “I am of the opinion that those who market Ginkgo biloba as a substance that sustains, enhances, or maintains memory need to provide evidence of that claim; our data suggest it is a claim with little or no foundation, and I would prefer to see such claims removed from packaging when they are unwarranted and unsupported.”
However, the meta-analysis differed from the GuidAge clinical trial in that it examined studies specifically for cognitive enhancement, not AD prevention. The 28 trials included in the meta-analysis featured different doses of various ginkgo extracts such as Li 1370 (Lichtwer Pharma AG; Berlin, Germany) and Blackmores (Warriewood, Australia), in addition to EGb 761. Although the marketing materials and/or labels of many ginkgo formulations claim to have cognitive enhancing properties (e.g., for improving mental sharpness, memory, and concentration12) in healthy populations, EGb 761 is marketed in numerous countries as a licensed or registered medicinal agent specifically for the treatment of dementia. The target group of EGb 761, according to Schwabe’s website, “includes patients with demential syndrome in primary degenerative dementia, vascular dementia, and mixed forms of both,” not healthy individuals hoping to prevent Alzheimer’s disease.13
Dr. Laws acknowledged that ginkgo extract might have an impact in people already suffering from dementia. “Ginkgo biloba may have a quite different role in Alzheimer’s. Meta-analyses (e.g. Weinmann et al. 2010)14 do indicate that Ginkgo biloba may have some beneficial effects on the cognition of those who already have Alzheimer’s disease,” he explained. “So [it] may not prevent transition to Alzheimer’s disease, but does appear to benefit patient cognitive abilities once people have actually developed the disease. The issue then becomes … for how long and to what degree, and these questions require further investigation.”
Future Research and Ginkgo Safety
Kelly Harrison, PhD, an instructor in the Department of Psychology at Virginia Tech University, noted a number of such dementia treatment studies. “Wang et al. (2010)15 performed a meta-analysis on the use of ginkgo in the treatment of dementia in which subjects took the preparation for six months and found a significant difference in favor of ginkgo,” she said (email, October 26, 2012). “Once again, this was a study looking for improvement in those already diagnosed with dementia, not ‘healthy populations.’ Similar results were found by Yang et al. (2011).16 I would suggest that the modest improvements found in some clinical trials are as frequent in the literature as are those that find no significant change. Such is the nature of scientific inquiry.”
According to Dr. Bruno Vellas, the lead author of the GuidAge trial, more research needs to be conducted before the effects of Ginkgo biloba on AD prevention can be stated with any certainty. “We think that the ginkgo hypothesis is still open and more studies have to be done,” he said (email, October 22, 2012).
Dr. Harrison noted that researchers should account for conventional pharmaceutical medications taken by participants, many of whom are elderly, through blood draws and analyses to help determine the blood levels of ginkgo’s primary active ingredients. “One in three of the elderly uses five or more prescription medications regularly, and about half use over-the-counter medications and dietary supplements,” she said. “Thus each person could actually be receiving an individualized dosage based on the number of drugs they are taking that interfere with ginkgo’s conversion. This may account for a lot of the variability in the herb’s performance and certainly deserves consideration before writing the drug off as a wash.”
Bill Gurley, PhD, a professor of pharmaceutical sciences at the University of Arkansas for Medical Science’s College of Pharmacy, agreed that adding blood work to such long-term clinical trials would be beneficial. “Having blood data to confirm compliance would certainly have been helpful, but the samples have to be taken at the appropriate times,” he said (email, November 5, 2012). “Too many clinical studies fail to measure phytochemical levels to confirm compliance at best and efficacy at least.”
Dr. Weber, too, sees room for improvement in future clinical trials. “In my opinion the failure of EGb 761 to show an effect in prevention trials for dementia might not so much be a problem of EGb 761 but rather a problem of dementia prevention trials,” he said. “Compliance is very difficult to achieve over a period of four or five years.”
Dr. Vellas, in the GuidAge paper’s conclusion, suggested that future trials “should use new methods, such as less burdensome cognitive assessments or home visits to reduce the number of non-completers, and should include new biomarker and imaging surrogate outcomes when these have been developed and validated.”3
Although various pharmaceutical drugs have been developed in recent years to combat AD, unpleasant side effects and limited effectiveness have prompted the investigation of alternatives such as ginkgo extract. And, despite differing interpretations of the GuidAge trial, the safety of EGb 761 has not been questioned. Researchers found no significant differences between ginkgo extract and placebo in terms of reported adverse events.3
“Our products are tested extensively and EGb 761 is in fact [one of the] best researched herbal extracts worldwide,” said Dr. Weber. “From numerous clinical and preclinical trials and also by the sheer number of users we know for sure that it is a very safe product.”
Dr. Cott says that despite the conventional medications or supplements one is taking, safety and tolerability should be a primary concern. “One should always do this risk/benefit analysis when considering a medication,” he said. “In a situation where one weighs the potential benefits against the known side effects and/or harms, ginkgo is a strong contender.”
1. What is Alzheimer’s? Alzheimer’s Association website. Available at: www.alz.org/alzheimers_disease_what_is_alzheimers.asp. Accessed October 26, 2012.
2. About Alzheimer’s disease: Alzheimer’s basics. National Institute on Aging website. Available at: www.nia.nih.gov/alzheimers/topics/alzheimers-basics. Accessed October 26, 2012.
3. Vellas B, Coley N, Ousset PJ, et al. Long-term use of standardized Ginkgo biloba extract for the prevention of Alzheimer’s disease (GuidAge): a randomized placebo-controlled trial. The Lancet Neurology. 2012;11(10):851-859. Available at: www.thelancet.com/journals/laneur/article/PIIS1474-4422(12)70206-5/abstract. Accessed October 16, 2012.
4. Reitz C. Alzheimer’s disease and the amyloid cascade hypothesis: a critical review. Int J of Alzheimer’s Disease. 2012. Published online March 17, 2012. doi: 10.1155/2012/369808. Available at: www.hindawi.com/journals/ijad/2012/369808/. Accessed November 26, 2012.
5. Tchantchou F, Xu Y, Wu Y, Christen Y, Luo Y. EGb 761 enhances adult hippocampal neurogenesis and phosphorylation of CREB in transgenic mouse model of Alzheimer’s disease. FASEB J. 2007;21.
6. Tchantchou F, Lacor PN, Cao Z, et al. Stimulation of neurogenesis and synaptogenesis by bilobalide and quercetin via common final pathway in hippocampal neurons. Journal of Alzheimer’s Disease. 2009;18:787–798.
7. Luo Y, Smith JV, Paramasivam V, et al. Inhibition of amyloid-β aggregation and caspase-3 activation by the Ginkgo biloba extract EGb761. PNAS. 2002;12197-12202.
8. Wu Y, Wu Z, Butko P, et al. Amyloid-β-induced pathological behaviors are suppressed by Ginkgo biloba extract EGb 761 and ginkgolides in transgenic Caenorhabditis elegan. Journal of Neuroscience. 2006; 13102-13113.
9. Product Monograph: EGb 761®. Dr. Willmar Schwabe Pharmaceuticals.
10. Schneider LS. Ginkgo and AD: key negatives and lessons from GuidAge. The Lancet Neurology. 2012;11(10):836-837. Available at: www.thelancet.com/journals/laneur/article/PIIS1474-4422(12)70212-0/fulltext. Accessed October 29, 2012.
11. Laws KR, Sweetnam H, and Kondel TK. Is Ginkgo biloba a cognitive enhancer in healthy individuals? A meta-analysis. Human Psychopharmacology. Published online September 24, 2012. doi:10.1002/hup.2259.
12.GinkGold®. Nature’s Way website. Available at: www.naturesway.com/Products/Herbs/6725-Ginkgold.aspx. Accessed November 1, 2012.
13.Tebonin® - EGb 761®. Schwabe Pharmaceuticals website. Available at: www.schwabepharma.com/international/products/tebonin/index.php. Accessed October 26, 2012.
14.Weinmann S, Roll S, Schwarzback C, Vauth C, and Willich SN. Effects of Ginkgo biloba in dementia: systematic review and meta-analysis. BMC Geriatrics. Published online March 17, 2012. doi: 10.1186/1471-2318-10-14. Available at: www.ncbi.nlm.nih.gov/pmc/articles/PMC2846949/. Accessed October 26, 2012.
15.Wang BS, Wang H, Song YY et al. Effectiveness of standardized Ginkgo biloba extract on cognitive symptoms of dementia with a six-month treatment: A bivariate random effect meta-analysis. Pharmacopsychiatry. 2012;44(3):86-91. Available at: www.ncbi.nlm.nih.gov/pubmed/20104449. Accessed October 29, 2012.
16.Yang Z, Li W, Huang T, Chen J, Zhang X. Meta-analysis of Ginkgo biloba extract for the treatment of Alzheimer’s disease. Neural Regeneration Research. 2011;6(15):1125-1129. Available at: www.ncbi.nlm.nih.gov/pubmedhealth/PMH0032313/. Accessed October 29, 2012.