Ginkgo Biloba supplementation has no effect on cognitive decline (but it does have other impacts)

If you are a supplement follower, you may have already read a newspaper article today on the major study on Ginkgo and cognition just reported in JAMA.  Here is a firsthand copy of the abstract of the original article Ginkgo biloba for Preventing Cognitive Decline in Older Adults – A Randomized Trial:

“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.

Results  Annual rates of decline in z scores did not differ between G biloba and placebo groups in any domains, including memory (0.043; 95% confidence interval [CI], 0.034-0.051 vs 0.041; 95% CI, 0.032-0.050), attention (0.043; 95% CI, 0.037-0.050 vs 0.048; 95% CI, 0.041-0.054), visuospatial abilities (0.107; 95% CI, 0.097-0.117 vs 0.118; 95% CI, 0.108-0.128), language (0.045; 95% CI, 0.037-0.054 vs 0.041; 95% CI, 0.033-0.048), and executive functions (0.092; 95% CI, 0.086-0.099 vs 0.089; 95% CI, 0.082-0.096). For the 3MSE and ADAS-Cog, rates of change varied by baseline cognitive status (mild cognitive impairment), but there were no differences in rates of change between treatment groups (for 3MSE, P = .71; for ADAS-Cog, P = .97). There was no significant effect modification of treatment on rate of decline by age, sex, race, education, APOE*E4 allele, or baseline mild cognitive impairment (P > .05).

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.”

Because of the size and controlled nature of the study, I can find no reason to challenge its conclusions.  In fact the conclusions are compatible with those of a January 2007 review study Ginkgo biloba for cognitive impairment and dementia. “AUTHORS’ CONCLUSIONS: Ginkgo biloba appears to be safe in use with no excess side effects compared with placebo. Many of the early trials used unsatisfactory methods, were small, and we cannot exclude publication bias. The evidence that Ginkgo has predictable and clinically significant benefit for people with dementia or cognitive impairment is inconsistent and unconvincing.”

The completely negative results are somewhat puzzling to me however, given a number of earlier research studies indicating that ginkgo biloba extract EGb 761, the same one used in the latest study,  has a capacity to promote neurogenesis in the hippocampus and improves cognitive functioning in small-animal models of Alzheimer’s disease.  For example:

·          The 2008 article Ginkgo Extract Has Multiple Actions on Alzheimer Symptoms, for example, states:  “In ongoing studies, a research team led by Luo found that giving mice with the human Alzheimer’s gene the ginkgo extract called EGb 761 improved the process of making new nerve cells in part of the brain much affected by the disease. The team found evidence that the protective effect of the extract also could be due to decreasing senile plaques or the clumping of beta-amyloid in the brain tissues.”  

·         Another relevant research report is the 2007 publication EGb 761 enhances adult hippocampal neurogenesis and phosphorylation of CREB in transgenic mouse model of Alzheimer’s disease. “The present findings suggest that 1) enhanced neurogenesis by EGb 761 may be mediated by activation of CREB, 2) stimulation of neurogenesis by EGb 761 may contribute to its beneficial effects in AD patients and improved cognitive functions in the mouse model of AD, and 3) EGb 761 has therapeutic potential for the prevention and improved treatment of AD.” 

·         The 2003 report Prenatal exposure of rats to Ginkgo biloba extract (EGb 761) increases neuronal survival/growth and alters gene expression in the developing fetal hippocampus states “These findings, which have provided the first genetic profile of the effects of EGb 761 on the developing rat hippocampus, increase our understanding of the molecular and genetic programs that are activated by the extract. These effects of EGb 761 may underlie its neuroprotective properties.” 

·         Studies of the neuroprotective effects of EGb 761 relating to Alzheimer’s Disease go back some time.  For example the 2000 publication The Ginkgo biloba extract (EGb 761) protects hippocampal neurons against cell death induced by beta-amyloid reported test-tube findings.  “We have investigated here the potential effectiveness of EGb 761 against toxicity induced by (Abeta)-derived peptides (Abeta25-35, Abeta1-40 and Abeta1-42) on hippocampal primary cultured cells, this area being severely affected in AD. A co-treatment with EGb 761 concentration-dependently (10-100 microg/mL) protected hippocampal neurons against toxicity induced by Abeta fragments, with a maximal and complete protection at the highest concentration tested.” 

·          The 2009 report Stimulation of Neurogenesis and Synaptogenesis by Bilobalide and Quercetin via Common Final Pathway in Hippocampal Neurons “Among the constituents tested, bilobalide and quercetin significantly increased cell proliferation in the hippocampal neurons in a dose-dependent manner. Bilobalide and quercetin also enhanced phosphorylation of cyclic-AMP Response Element Binding Protein (CREB) in these cells, and elevated the levels of pCREB and, brain-derived neurotrophic factor in mice brain. Immunofluorescence staining of synaptic markers shows remarkable dendritic processes in hippocampal neurons treated with either quercetin or bilobalide. Furthermore, both constituents restored amyloid-β oligomers (also known as ADDL)-induced synaptic loss and phosphorylation of CREB. The present findings suggest that enhanced neurogenesis and synaptogenesis by bilobalide and quercetin may share a common final signaling pathway mediated by phosphorylation of CREB. Despite a recent report showing that EGb 761 was insufficient in prevent dementia, its constituents still warrant future investigation.”

This all leaves me is thinking:

·        Despite the negative clinical studies related to cognition and dementia, there is much more to ginkgo biloba extract EGb 761 than vitamin-marketing smoke-and-mirrors.

·        I find the results of the large-scale human clinical study hard to understand given the results of the earlier animal studies but, hey, we are not rats and science is science.

·        For the present, I want to avoid any further claim that ginkgo biloba extract supplementation can prevent dementia or enhance cognition.

·        Until I can review the issue in more detail, I am leaving ginkgo biloba extract  as part of my Anti-aging firewalls supplement regimen because of possible health-giving actions the substance may have above and beyond cognition enhancement or dementia prevention.  For example, see Studies on the effect of Ginkgo biloba extracts on NF-kappaB pathway,  Ginkgo biloba Extract Inhibits Tumor Necrosis Factor- –Induced Reactive Oxygen Species Generation, Transcription Factor Activation, and Cell Adhesion Molecule Expression in Human Aortic Endothelial Cells and Ginkgo biloba extract reduces endothelial progenitor-cell senescence through augmentation of telomerase activity.