No Benefit of Ginkgo Biloba for Age-Related Cognitive Decline

Susan Jeffrey

December 30, 2009

December 30, 2009 — Results of a randomized trial show no effect of ginkgo biloba supplements on the rate of cognitive decline in adults with either normal cognition or mild cognitive impairment.

The Ginkgo Evaluation of Memory (GEM) study, a large randomized trial, showed that use of the popular herbal supplement in a dose of 120 mg twice daily was no different than placebo in terms of cognitive outcomes during a median follow-up of 6 years.

"There were changes of normal aging in the general testing and in all 4 cognitive domains, but there was no separation between the 2 curves; they were virtually completely superimposable," senior author Steven T. DeKosky, MD, from the University of Pittsburgh, Pennsylvania, told Medscape Neurology.

The study is published in the December 23/30 issue of the Journal of the American Medical Association.

No Effect on Alzheimer's

Ginkgo biloba is among the most widely used complementary alternative medicines and is taken for a variety of reasons, among them the preservation of cognitive health in aging, the authors note. The primary analysis of the GEM study, published in 2008, showed that treatment with ginkgo in a dose of 120 mg twice daily had no effect in reducing the incidence of Alzheimer's dementia or all-cause dementia in subjects without dementia at baseline (DeKosky ST, et al. JAMA 2008;300:2253-2262).

In the present analysis, an a priori secondary outcome of the GEM study, the authors looked at data on the rate of change over time in cognitive outcomes among 3069 community-dwelling subjects who were aged 72 to 96 years and who had either normal cognitive function or mild cognitive impairment at baseline.

Participants were randomly assigned to receive a 120-mg dose twice daily of either ginkgo biloba extract or placebo and were followed-up for a median of 6.1 years. Outcomes of interest were rates of change over time in the Modified Mini-Mental State Examination and the cognitive subscale of the Alzheimer's Disease Assessment Scale and in the neuropsychological domains of memory, attention, visual-spatial construction, language, and executive functions, based on the sums of z scores of these individual tests.

"We did certainly find some changes in the normal group in their activities [and] in their overall cognitive function, as well as in memory, visual-spatial function, executive function, and so forth, but we found no differences between the performance in those who took the ginkgo and those who were on placebo," Dr. DeKosky said.

GEM: Annual Rates of Decline With Ginkgo Biloba vs Placebo

Domain Annual Rate of Decline in z Scores With Ginkgo Biloba (95% confidence interval) Annual Rate of Decline in z Scores With Placebo (95% confidence interval)
Memory 0.043 (0.034 - 0.051) 0.041 (0.032 - 0.050)
Attention 0.043 (0.037 - 0.050) 0.048 (0.041 - 0.054)
Visuospatial abilities 0.107 (0.097 - 0.117) 0.188 (0.108 - 0.128)
Language 0.045 (0.037 - 0.054) 0.041 (0.033 - 0.048)
Executive functions 0.092 (0.086 - 0.099) 0.089 (0.082 - 0.096)

Rates of change on the Modified Mini-Mental State Examination and the cognitive subscale of the Alzheimer's Disease Assessment Scale varied by baseline cognitive status, but there were no differences in the rates of change between treatment groups. Similarly, there was no significant effect modification of treatment on the rate of decline by factors including age, sex, race, education, presence or absence of the APOE*E4 risk allele, or mild cognitive impairment at baseline.

Treatment appeared to be safe, however, with no evidence seen of gastrointestinal problems or increased bleeding risk with active treatment.

Dr. DeKosky pointed out that their results apply to an older population and to a largely Caucasian cohort. For this population, however, it seems clear that ginkgo does not have an effect — there was no separation of the curves at any point that might hint, for example, that an effect might have become clear with longer follow-up.

"I think we're more disappointed than anything, but we continue to look for things that work," Dr. DeKosky said in an interview. For example, another supplement, called huperzine — an extract of Chinese tea with properties similar to cholinesterase inhibitors — is under evaluation now for the treatment of Alzheimer's disease.

Still, some people will want to continue to take ginkgo, and as it is safe and relatively inexpensive, it probably would not be a problem to do so, Dr. DeKosky noted. "I don't believe in getting into disagreements with my patients who'd like to do something more than whatever we have to offer," he said. Instead, he encourages patients to go through a series of questions about the proposed treatment: Is it safe? Are there data to support its use? Does it cross-react with other medications they are taking? Is it sufficiently expensive to produce hardship?

Ginkgo biloba is still being investigated in a number of other indications, including cardiovascular disease and tinnitus, he added, "but so far, for the cognitive indications, we have not been able to determine a positive effect."

A "Nail in the Coffin"

Asked for comment on these findings, Ronald Devere, MD, director of the Alzheimer's Disease and Memory Disorders Center in Austin, Texas, and a fellow of the American Academy of Neurology, pointed out that ginkgo has been used for many years to prevent age-related cognitive decline. Possible mechanisms of action of ginkgo in this setting include increases in cerebral blood flow by cerebrovascular relaxation or a decrease in blood viscosity or in oxygen free radicals, among others, he noted.

The current analysis is part of the GEM study, the largest randomized trial of ginkgo biloba vs placebo to date that showed no effect of active treatment on slowing the development of either Alzheimer's disease or other dementias, Dr. Devere noted, or now in the rate of change in those with normal cognition or mild cognitive impairment.

"Numerous other, smaller studies have shown the same outcome but were limited by small size and shorter follow-up than reported in this article," Dr. Devere told Medscape Neurology. The only limitations of the study were that it did not include enough ethnic or other cultural groups to make conclusions about these populations and that it included a fairly highly educated group.

"Despite these mild limitations, it is a sound study and all but puts a final nail in the coffin of using [ginkgo biloba] to help prevent cognitive decline in the normal or mild cognitively impaired elderly," Dr. Devere concluded. "This study does not give us any definitive information in the normal younger or middle-aged population, some of whom may already be developing the early brain changes of Alzheimer's disease or other dementias."

The study was funded by a grant from the National Center for Complementary and Alternative Medicine, the Office of Dietary Supplements, and by support from the National Institute on Aging, National Heart, Lung, and Blood Institute, University of Pittsburgh Alzheimer's Disease Research Center, Roena Kulynych Center for Memory and Cognition Research, and National Institute of Neurological Disorders and Stroke. Dr. DeKosky reports receiving grants or research support from Elan, Myriad, Neurochem, and GlaxoSmithKline, and serving on the advisory boards of or consulting for AstraZeneca, Abbott, Baxter, Daichi, Esai, Forest, Genentech, GlaxoSmithKline, Lilly, Medivation, Merck, NeuroPharma, Neuroptix, Pfizer, Myriad, and Servier. Disclosure information for coauthors appears in the article.

JAMA. 2009;302:2663-2670.

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