Journal of the American Medical Association
Vol. 302 No. 24, December 23/30, 2009
A Randomized Trial
ABSTRACT
Context The herbal product Ginkgo biloba is taken frequently with the intention of improving cognitive health in aging. However, evidence from adequately powered clinical trials is lacking regarding its effect on long-term cognitive functioning.
Objective To determine whether G biloba slows the rates of global or domain-specific cognitive decline in older adults.
Design, Setting, and Participants The Ginkgo Evaluation of Memory (GEM) study, a randomized, double-blind, placebo-controlled clinical trial of 3069 community-dwelling participants aged 72 to 96 years, conducted in 6 academic medical centers in the United States between 2000 and 2008, with a median follow-up of 6.1 years.
Intervention Twice-daily dose of 120-mg extract of G biloba (n = 1545) or identical-appearing placebo (n = 1524).
Main Outcome Measures Rates of change over time in the Modified Mini-Mental State Examination (3MSE), in the cognitive subscale of the Alzheimer Disease Assessment Scale (ADAS-Cog), and in neuropsychological domains of memory, attention, visual-spatial construction, language, and executive functions, based on sums of z scores of individual tests.
Conclusion Compared with placebo, the use of G biloba, 120 mg twice daily, did not result in less cognitive decline in older adults with normal cognition or with mild cognitive impairment.
Trial Registration clinicaltrials.gov Identifier: NCT00010803
INTRODUCTION
Ginkgo biloba is marketed widely and used with the hope of improving, preventing, or delaying cognitive impairment associated with aging and neurodegenerative disorders such as Alzheimer disease. The primary outcome analysis from the Ginkgo Evaluation of Memory (GEM) study, the largest completed randomized, double-blind, placebo-controlled dementia prevention trial to date,1 found that G biloba, 120 mg twice daily, was not effective in reducing the incidence of Alzheimer dementia or dementia overall.
Beyond consideration of a clinical dementia outcome, however, it is possible that G biloba may have had more subtle, therapeutic effects on the rate of cognitive change. Specifically, G biloba may have prevented or delayed age-related changes in individuals with normal cognition, or G biloba may have slowed the rate of decline in those characterized as having mild cognitive impairment (MCI). Indeed, in the United States and particularly in Europe, G biloba is perhaps the most widely used herbal treatment consumed specifically to prevent age-related cognitive decline.2 Putative mechanisms of action on brain functioning include vascular effects such as cerebral vasorelaxation and reduction of blood viscosity,3-4 reduction of oxygen free radicals,5 and neurotransmitter system effects.6-7 Moreover, some in vitro studies indicate that G biloba may inhibit amyloid aggregation, suggesting another mechanism of preventing or delaying cognitive decline associated with Alzheimer disease.8
To date, adequately powered, longer-duration clinical trials testing the effect of G biloba on the rate of cognitive decline in aging have been lacking. Most reported human studies of the cognitive effects of G biloba in individuals without dementia have been restricted by very small samples and limiting design features9 such as acute administration,10-12 short-term treatment intervals,13 combinations of agents,14 or study of younger healthy volunteers.11, 14
[For additional text see original article at JAMA]
COMMENT
This study examined whether a twice-daily 120-mg dose of G biloba affected the rate of cognitive change over time in older adults. We found no evidence for an effect of G biloba on global cognitive change and no evidence of effect on specific cognitive domains of memory, visual-spatial construction, language, attention and psychomotor speed, and executive functions. We found also no evidence for differences in treatment effects by age, sex, race, education, APOE*E4 allele status, or baseline cognitive status (MCI vs normal cognition). The observation of no significant effect modification by baseline cognitive status suggests that G biloba affected neither subtle preclinical cognitive changes associated with dementia prodrome nor cognitive changes associated with normal aging. Consistent with this conclusion is the alternative analysis in which the baseline was shifted to study year 6. By censoring the early period of the study, participants with early dementia or dementia prodrome who had reached a study end point were excluded. Results of this analysis indicate that 3 to 4 years of prior G biloba treatment had no significant effect on cognitive decline over the subsequent 2 to 3 years in older adults who were most likely not in a dementia prodrome at the beginning of the trial.
The present results are consistent with smaller trials. Solomon et al32 reported that in a 6-week, placebo-controlled, double-blind clinical trial among 219 older adults, G biloba (120-mg daily dose) did not facilitate performance on standard neuropsychological tests of memory, attention, or language. A feasibility trial by Dodge et al33 randomized 118 older adults (mean age, 87 years) to 240 mg/d of G biloba vs placebo and reported no difference in episodic memory decline during an average follow-up of 3.5 years in an intention-to-treat analysis. However, the statistical significance of the treatment effect was borderline (P = .05), and a secondary adherence analysis suggested a smaller decline in memory scores in the G biloba group (P = .04). Memory was the only cognitive domain evaluated by Dodge et al.
The GEM study is the largest randomized controlled trial of G biloba to report on outcomes to date. Strengths of this study include the large number of randomized participants (n = 3069), long duration of follow-up (median of 6 years), and breadth of the neuropsychological evaluation, including measurement of multiple cognitive domains. The estimated power to detect a reliable difference in the rates of cognitive decline was high, as reflected by the 95% CIs reported in Table 2. For example, with regard to global cognition, we had sufficient power to rule out a difference of more than 0.009 SDs per year favoring the treatment group relative to the placebo group at the 95% confidence level. With regard to memory, a difference of more than 0.010 SDs per year favoring the treatment group relative to the placebo group can be confidently ruled out.
A final point to consider is the clinical meaning of decline in this study. A 4-point change in the ADAS-Cog score is considered clinically significant within the context of treatment trials in Alzheimer disease. By comparison, the annual change in ADAS-Cog scores in this study was observed to be 0.32 points within participants characterized as having MCI, a much slower rate of decline. The rates of change we observed in the 3MSE also were small and not clinically significant, though they are consistent with other studies of generally healthy older adults.34-35
In sum, we find no evidence that G biloba slows the rate of cognitive decline in older adults. These findings are consistent with previous smaller studies examining prevention of decline33 and facilitation of cognitive performance32 and with the 2009 Cochrane review of G biloba for dementia and cognitive impairment.36
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