No Go? Ginkgo and Dementia

Abstract & Commentary

By Russell H. Greenfield, MD, Editor

Synopsis: In this re-examination of data from the large GEM study of Ginkgo biloba in elderly subjects and incident dementia, the investigators suggest that ginkgo not only does not prevent the development of dementia, but also does not slow the rate of cognitive decline in old age. The study is impressive in many ways, but methodological flaws noted when the original GEM data were first published, and others that have since come to light, suggest that the data actually have little clinical utility, except to suggest that the very old not use ginkgo to help stave off cognitive decline. Whether use of ginkgo in younger, healthy subjects may have a brain protective effect in later years remains unknown.

Source: Snitz B, et al. Ginkgo biloba for preventing cognitive decline in older adults. A randomized trial. JAMA 2009;302: 2663-2670.

The findings in this paper, a re-evaluation of data from the Ginkgo Evaluation of Memory (GEM) study (JAMA 2008;300:2253-2262; reviewed in the January 2009, issue of Alternative Medicine Alert), the largest randomized, double-blind, placebo-controlled dementia prevention trial to date that suggested ginkgo was not effective in reducing the incidence of dementia, has generated a great deal of controversy. In the current analysis, the researchers wanted to see whether ginkgo slowed the rate of cognitive decline in older adults, even if it didn't ultimately prevent the disease.

As a reminder, more than 3,000 people (mean age, 79 years; range, 72-96 years) with either normal or mildly impaired cognition (n = 482 with mild cognitive impairment [MCI]) participated in the GEM study. Subjects were randomized to receive either 120 mg Ginkgo biloba extract (EGb-761) or an identical placebo tablet twice daily. They were then assessed every 6 months for incident dementia using multiple tools, and employing DSM-IV criteria. After a median follow-up of 6.1 years, overall dementia rates were 3.3/100 years in the active group and 2.9/100 years in the placebo group. The hazard ratio for ginkgo use and all-cause dementia was 1.12, and 1.16 for Alzheimer's disease compared with placebo. The authors concluded that a standardized extract of Ginkgo biloba given in a commonly used dose does not reduce the overall incidence of dementia in seniors with normal cognitive function or those with MCI.

In the current re-evaluation, the investigators assessed rates of change over time on the Modified Mini-Mental State Examination (3MSE), in the cognitive subscale of the Alzheimer Disease Assessment Scale (ADAS-Cog), and in neurophysiological domains of memory, attention, visual-spatial construction, language, and executive functions. They found that the annual rates of decline in scores on these measures did not differ between those receiving ginkgo and those taking the placebo. They also determined that ginkgo had no differential effects on specific domains of cognition. The researchers concluded that a standardized extract of ginkgo in a dose of 120 mg twice daily offers no benefit over placebo with respect to lessening the incidence of cognitive decline in elderly subjects.

Commentary

As noted in the earlier review, this is a well-done study that offers some useful information about the potential utility, or lack thereof, of the very popular and highly regarded standardized extract of Ginkgo biloba known as EGb 761. That stated, it's important that the significant limitations inherent in the analysis are well-understood, so that the reach of the authors' conclusions is not unduly extended.

The GEM data suggest that ginkgo does not have a significant effect on the cognitive capacity of people older than age 80, on average, and that's important. Some prior data have suggested small benefits of ginkgo administration in this population, while others have not, so the evidence to date has not been compelling. Likewise, research into the use of ginkgo in healthy younger people over relatively short periods of time has not provided strong suggestion of cognitive benefit, so the current findings would not seem out of line with previous understanding of ginkgo's clinical efficacy. However, it's important to remember that in the GEM trial ginkgo was not initiated until the subjects were well into their 70s and 80s, or older, so we do not know if a longer duration of ginkgo administration started earlier in life would have offered a primary preventive effect.

Additional methodological challenges to adoption of the researchers' conclusions exist. The incidence of dementia in the cohort was well below that expected, and 40% of those in the ginkgo group were not compliant with therapy. Some experts are also taking issue with extending the findings of relatively nonspecific tests of cognition to very specific clinical outcomes of cognitive function over a relatively brief period of time.

Our population is graying and the incidence of dementia is primed to increase dramatically. Drug therapy already approved for use against dementia offers, at best, inconsistent benefits. Existing research on the use of ginkgo also suggests mild, albeit inconsistent, benefit, yet it remains one of the most popular botanical remedies in the world. Can millions of people be wrong? Yes, but the findings of research studies sometimes are wrongly interpreted, too, especially when methodological concerns seem justified.

Is it time to close the book on the use of ginkgo as a preventive or treatment for dementia? The data on ginkgo's use as treatment for dementia in the elderly are weak, but the potential for a preventive benefit in younger subjects has yet to be definitively determined, and the current study ultimately adds little to what was already known in this regard.