. 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.

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  1. This work adds to the therapeutic rationale for the standardized ginkgo biloba extract EGb 761—sold as a dietary food supplement in the U.S.—or some of its components as potential treatments for Alzheimer disease. APP transgenic mice were fed 300 mG/kG doses of EGb 761 that are 90 times greater than the 240 mG/day doses used in human clinical trials, and for over 16 months—a substantial proportion of the animals' lifespans. The investigators report 50 percent decreases in cerebral cortex APP but not hippocampal, suggesting that something in the extract targets APP, and may be related to any neuroprotective properties that the extract might have.

    Other preclinical work suggests specific "anti-Aβ" effects of the ginkgolides A and J identified in the standardized leaf extracts, that they variously inhibit Aβ42-induced hippocampal neuron dysfunction and death (1,2), decrease Aβ42-induced pathological behaviors, (3) enhance neurogenesis, (4) and inhibit Aβ aggregation (5).

    Yet the substantial body of unbiased clinical trials data—when systematically examined as a whole and not cherry-picked for individually significant trials—indicates the lack of evidence for efficacy of the same EGb 761 ginkgo extracts for enhancing cognition in unimpaired elderly (6), in patients with Alzheimer disease (7), or most recently in the prevention of Alzheimer disease (in press at JAMA).

    There is a disconnect between our preclinical to translational research efforts here. Perhaps the relevant active therapeutic molecules haven't been identified. Given the substantial dosing differences between the animal models and humans, maybe the doses humans used are not relevant. If there is a future for ginkgo biloba extracts as a therapeutic for AD, then it has to depend on the development of the individual ginkgolides and flavonoids, or perhaps on using much higher doses of extract in humans. The barriers to the development include the lack of patent protection and profit incentive. In any event, it would be a mistake to advocate for the continued use of ginkgo biloba extract based on the hope that it may in some way be helpful.

    References:

    . The Ginkgo biloba extract (EGb 761) protects hippocampal neurons against cell death induced by beta-amyloid. Eur J Neurosci. 2000 Jun;12(6):1882-90. PubMed.

    . Protection against beta-amyloid induced abnormal synaptic function and cell death by Ginkgolide J. Neurobiol Aging. 2009 Feb;30(2):257-65. PubMed.

    . Amyloid-beta-induced pathological behaviors are suppressed by Ginkgo biloba extract EGb 761 and ginkgolides in transgenic Caenorhabditis elegans. J Neurosci. 2006 Dec 13;26(50):13102-13. PubMed.

    . EGb 761 enhances adult hippocampal neurogenesis and phosphorylation of CREB in transgenic mouse model of Alzheimer's disease. FASEB J. 2007 Aug;21(10):2400-8. PubMed.

    . Inhibition of amyloid-beta aggregation and caspase-3 activation by the Ginkgo biloba extract EGb761. Proc Natl Acad Sci U S A. 2002 Sep 17;99(19):12197-202. PubMed.

    . Ginkgo biloba is not a smart drug: an updated systematic review of randomised clinical trials testing the nootropic effects of G. biloba extracts in healthy people. Hum Psychopharmacol. 2007 Jul;22(5):265-78. PubMed.

    . Ginkgo biloba for cognitive impairment and dementia. Cochrane Database Syst Rev. 2009;(1):CD003120. PubMed.

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