The trial, headed by Steven DeKosky, who is now dean of the University of Virginia School of Medicine, Charlottesville, showed that daily doses of a commonly used, standardized ginkgo biloba leaf extract taken over six years did not delay the development of dementia or Alzheimer disease in 1,545 treated seniors who started with no or minor memory loss. The results appear in the November 19 issue of JAMA.

In an editorial accompanying the research report, Lon Schneider of the University of Southern California, Los Angeles, writes, “The GEM (Ginkgo Evaluation of Memory) study adds to the substantial body of evidence that G. biloba extract as it is generally used does not prevent dementia in individuals with or without cognitive impairment and is not effective for Alzheimer disease.” He continues, “Users of this extract should not expect it to be helpful.”

Ginkgo biloba extracts are widely touted, and taken, as cognitive enhancers. Recent biological studies suggested a rationale for their use in prevention or treatment of AD. The extracts have antioxidant activity, and counteract the aggregation or deposition of amyloid-β in vitro and in animal models (see, e.g., Augustin et al., 2008 and associated comment). These preclinical hints, however, had not thus far been followed up with adequate trial data.

The GEM study (DeKosky et al., 2006), and a similarly sized trial still going on in Europe (Vellas et al., 2006), were designed to bridge that gap. The randomized, double-blind, placebo-controlled trial asked whether EGb 761, a commercial extract contained in many over-the-counter ginkgo preparations, at a dose of 120 mg twice a day, could delay the onset of dementia or Alzheimer disease in older adults. Participants included 2,587 cognitively normal elderly volunteers, and 482 with mild cognitive impairment (mean age for all, 79.1 years). Five different medical centers recruited and followed participants. Half received ginkgo and half got placebo. Subjects were assessed every six months for an average of 6.1 years. The measured endpoint was onset of dementia of any cause, or Alzheimer disease.

In the end, the researchers found no difference in the incidence of all-cause dementia, or AD in particular, between the ginkgo takers and the placebo group. They also found no serious adverse effects, although a higher number of hemorrhagic strokes occurred in the gingko group. However, the numbers in both groups were small and the difference was not significant. Nonetheless, this finding should be further studied, the authors conclude.

Another endpoint, cardiovascular disease, was likewise unaffected by ginkgo supplements. There was a higher incidence of dementia in ginkgo takers with existing cardiovascular disease, though, suggesting that older people with heart troubles might reconsider ginkgo use.

It is always possible that starting treatment earlier, i.e., in mid-life, or treating longer, would result in a different outcome, the authors consider. In addition, there is the chance that other gingko formulations, or some particular component of the extract given in higher doses, might be effective (e.g., see Vitolo et al., 2007). In the absence of more evidence for these scenarios, the authors conclude, “Based on the results of this trial, G. biloba cannot be recommended for the purpose of preventing dementia.”

The study results as presented did not address possible effects of ginkgo biloba as a memory enhancer in cognitively normal people. The GEM study did include measures of overall cognitive decline and disability as secondary outcomes, but the data are not reported in this paper. While it is unlikely that these endpoints would show a positive result while dementia was unchanged, having that data will be important to understand if ginkgo has an acute effect on memory. As Schneider writes in his editorial, “The effects of EGb 761 on actual cognitive test scores and daily function ratings are important because individuals without cognitive impairment who use G. biloba may expect it to noticeably improve their intellectual function in the short term but not necessarily to prevent Alzheimer disease or other dementias over the long term.”

There was some good news in the trial. Treatment adherence and follow-up, particular concerns with a large group of elderly subjects, were both good. At the end of the trial, 60 percent of subjects were still taking their pills faithfully, and more than 90 percent of participants were successfully followed to the end. This bodes well for future AD prevention trials that will need to recruit healthy adults from the community and track them for years.—Pat McCaffrey.

References:
Dekosky ST, Williamson JD, Fitzpatrick AL, Kronmal RA, Ives DG, Saxton JA, Lopez OL, Burke G, Carlson MC, Fried LP, Kuller LH, Robbins JA, Tracy RP, Woolard NF, Dunn L, Snitz BE, Nahin RL, Furberg CD; for the Ginkgo Evaluation of Memory (GEM) Study Investigators. Ginkgo biloba for Prevention of Dementia: A Randomized Controlled Trial. JAMA. 2008 Nov 19;300(19):2253-2262. Abstract

Schneider LS. Ginkgo biloba Extract and Preventing Alzheimer Disease JAMA. 2008 Nov 19;300(19):2306-2308.