Big Ginkgo Prevention Trial Comes Up Negative

Older people who are buying and taking ginkgo biloba pills to ward off Alzheimer disease can save their money, according to the results out this week from a large, multi-year prevention trial of the supplements in healthy 70 and 80 year olds.

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

Comments

  1. This is an important paper with an excellent accompanying editorial. This large study (more 2,500 subjects entering the study with "normal cognition" and almost 500 with MCI) with a good length of follow-up (~6years) did not show a benefit of Ginkgo biloba in terms of progression to dementia or AD in either the normal or MCI subjects. The study is important given the widespread use of Ginkgo.

    The fact that more than 3,000 subjects were willing to take part in this study in the hope that it might show a reduction in the incidence of dementia should remind us of the need for effective preventative therapies and of the the public's desire to help in that search.

    View all comments by Nick Fox

  2. This study reaches a high methodological standard. However, some minor comments bear consideration. Compared to the general population and other studies, the rate of female participants in this study is low (placebo 47, ginkgo 45 percent). The probability values in the group characteristics table need clarification of how they were calculated. For instance, there is a small difference in the number of diabetic patients in the placebo (138) and ginkgo (139) groups, a larger difference in the number of patients with MCI (226 on placebo, 256 on gingko), but for both, the P value is .18. The study investigates people 75 years and older and is limited to drug intake times shorter than seven years. Conclusions should take this into account.

    Many epidemiological studies show risk factors of Alzheimer disease, but unfortunately, only a few prospective studies are published and so far none has demonstrated a significant effect for any potentially risk-reducing behavior, or non-pharmaceutical or drug intervention.

    Previous studies have given hints of a preventive effect of ginkgo, for example, the EPIDOS study (Andrieu et al., 2003) and the PAQUID study (Dartigues et al., 2007; N = 3534, duration 13 years). In people older than 75, a prospective study was unable to support these findings. This does not change the statement that no intervention evidently prevents AD. However, at least for persons younger than 75, or with longer drug intake, the present study does not disprove these previous hints.

    Dementia is thought to start 10 years prior to clinical onset. The cause is still unknown but a yet-to-be-defined metabolic cascade is thought to lead to cell damage and cell death. Age might be one intervening variable that could help to explain the diverging results.

    Support for this assumption stems from studies in patients with dementia. The two negative studies included patients with a relative high mean age (Schneider et al., 2005: placebo 77.5 years, 120 mg ginkgo 78.6 years, 240 mg ginkgo 78.1 years; McCarney et al., 2008: placebo 79.7, ginkgo 79.3). The positive studies included younger patients (Kanowski et al., 1996: placebo and ginkgo 72 years; LeBars et al., 1997: placebo and ginkgo 68 years; Napryeyenko et al., 2007: placebo 64 years, ginkgo 66 years, and unpublished research funded by Wilmar Schwabe Arzneimittel, a German plant pharmaceutical company and manufacturer of gingko biloba: placebo and ginkgo 65 years). Further studies will have to test the assumption that gingko might provide some protection if taken at younger ages.

    Nearly coincidentally with this U.S. study, the German Institute for Quality and Efficiency in Health Care) on November 21 published its independent review of ginkgo in dementia. This review aimed to detect efficacy of ginkgo in treating dementia, not in prevention. The review constitutes a meticulous analysis of articles published in the field and selected only papers with no or minor flaws. Seven studies with a total of nearly 2,042 patients were included, 810 of them in Eastern Europe. Among these studies, the Schneider study was deemed to have no flaws, whereas the McCarney study only narrowly met inclusion criteria. Studies had to be placebo-controlled randomized controlled trials with a duration of at least 16 weeks investigating ginkgo in Alzheimer disease. The report is in German; hence, I provide a brief translation of the key conclusions:

    Therapeutic Aims
    1. Activities of daily living: patients treated with 240 mg daily have an demonstrated benefit.

    2. Cognition, psychopathological symptoms, quality of life of caregivers: there is an indication of benefit with the 240 mg dose.

    The conclusion of benefit is based on results in heterogeneous study populations. Study heterogeneity was significant and could not be explained sufficiently. Moreover, there is an indication that the therapeutic benefit might only be observable in patients with psychopathological symptoms. Two of the studies, accounting for 630 patients, come from the Ukraine, whose health and caregiving context differs from that in Western Europe. In Western countries, the benefits from gingko may be smaller than those seen in the Ukraine. The benefit of gingko compared to cholinesterase inhibitors and memantine is not clear. Only one explorative study directly compared gingko with donepezil.

    Regarding side effects, results were inconsistent. There was no indication of harm of ginkgo biloba; however, more patients on gingko than on placebo dropped out of the studies.

    Further studies are necessary, preferably in a Western context. Such studies might be difficult to carry out because of treatment with cholinesterase inhibitors. Hence, studies comparing different anti-dementia drugs are recommended. Moreover, data from long-term studies would be desirable to demonstrate efficacy and side effects of ginkgo biloba.

    References:

    Andrieu S, Gillette S, Amouyal K, Nourhashemi F, Reynish E, Ousset PJ, Albarede JL, Vellas B, Grandjean H, . Association of Alzheimer's disease onset with ginkgo biloba and other symptomatic cognitive treatments in a population of women aged 75 years and older from the EPIDOS study. J Gerontol A Biol Sci Med Sci. 2003 Apr;58(4):372-7. PubMed.

    Dartigues JF, Carcaillon L, Helmer C, Lechevallier N, Lafuma A, Khoshnood B. Vasodilators and nootropics as predictors of dementia and mortality in the PAQUID cohort. J Am Geriatr Soc. 2007 Mar;55(3):395-9. PubMed.

    Schneider LS, Dekosky ST, Farlow MR, Tariot PN, Hoerr R, Kieser M. A randomized, double-blind, placebo-controlled trial of two doses of Ginkgo biloba extract in dementia of the Alzheimer's type. Curr Alzheimer Res. 2005 Dec;2(5):541-51. PubMed.

    McCarney R, Fisher P, Iliffe S, van Haselen R, Griffin M, van der Meulen J, Warner J. Ginkgo biloba for mild to moderate dementia in a community setting: a pragmatic, randomised, parallel-group, double-blind, placebo-controlled trial. Int J Geriatr Psychiatry. 2008 Dec;23(12):1222-30. PubMed.

    Kanowski S, Herrmann WM, Stephan K, Wierich W, Hörr R. Proof of efficacy of the ginkgo biloba special extract EGb 761 in outpatients suffering from mild to moderate primary degenerative dementia of the Alzheimer type or multi-infarct dementia. Pharmacopsychiatry. 1996 Mar;29(2):47-56. PubMed.

    Le Bars PL, Katz MM, Berman N, Itil TM, Freedman AM, Schatzberg AF. A placebo-controlled, double-blind, randomized trial of an extract of Ginkgo biloba for dementia. North American EGb Study Group. JAMA. 1997 Oct 22-29;278(16):1327-32. PubMed.

    Napryeyenko O, Borzenko I, . Ginkgo biloba special extract in dementia with neuropsychiatric features. A randomised, placebo-controlled, double-blind clinical trial. Arzneimittelforschung. 2007;57(1):4-11. PubMed.

    View all comments by Ralf Ihl

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References

Paper Citations

  1. Augustin S, Rimbach G, Augustin K, Schliebs R, Wolffram S, Cermak R. Effect of a short- and long-term treatment with Ginkgo biloba extract on amyloid precursor protein levels in a transgenic mouse model relevant to Alzheimer's disease. Arch Biochem Biophys. 2009 Jan 15;481(2):177-82. PubMed.
  2. Dekosky ST, Fitzpatrick A, Ives DG, Saxton J, Williamson J, Lopez OL, Burke G, Fried L, Kuller LH, Robbins J, Tracy R, Woolard N, Dunn L, Kronmal R, Nahin R, Furberg C, . The Ginkgo Evaluation of Memory (GEM) study: design and baseline data of a randomized trial of Ginkgo biloba extract in prevention of dementia. Contemp Clin Trials. 2006 Jun;27(3):238-53. PubMed.
  3. Vellas B, Andrieu S, Ousset PJ, Ouzid M, Mathiex-Fortunet H, . The GuidAge study: methodological issues. A 5-year double-blind randomized trial of the efficacy of EGb 761 for prevention of Alzheimer disease in patients over 70 with a memory complaint. Neurology. 2006 Nov 14;67(9 Suppl 3):S6-11. PubMed.
  4. Vitolo O, Gong B, Cao Z, Ishii H, Jaracz S, Nakanishi K, Arancio O, Dzyuba SV, Lefort R, Shelanski M. Protection against beta-amyloid induced abnormal synaptic function and cell death by Ginkgolide J. Neurobiol Aging. 2009 Feb;30(2):257-65. PubMed.

Further Reading

Papers

  1. Cao Z, Wu Y, Curry K, Wu Z, Christen Y, Luo Y. Ginkgo biloba extract EGb 761 and Wisconsin Ginseng delay sarcopenia in Caenorhabditis elegans. J Gerontol A Biol Sci Med Sci. 2007 Dec;62(12):1337-45. PubMed.

News

  1. Gingko Is a No-Go

Primary Papers

  1. 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, . Ginkgo biloba for prevention of dementia: a randomized controlled trial. JAMA. 2008 Nov 19;300(19):2253-62. PubMed.
  2. Schneider LS. Ginkgo biloba extract and preventing Alzheimer disease. JAMA. 2008 Nov 19;300(19):2306-8. PubMed.

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