Age-related cognitive decline is one of the main challenges of mental health research. As no curative treatment for dementia presently exists, an alternative would be to find strategies that could contribute to attenuating cognitive decline in the elderly, which could in turn possibly delay the onset of dementia. A large number of interventional or observational studies have looked at the potential benefits of various pharmacological treatments. In particular, drugs controlling vascular factors such as statins have received much attention as a result of the growing emphasis on the vascular component of dementia and cognitive decline. However, these studies have yielded contrasting results 
. As the neurodegenerative process is accompanied by exacerbated oxidative stress, anti-oxidant vitamins have also been considered as good candidates 
. Even if the results of the few studies reporting potential benefits of vitamin E, beta-carotene or multi-vitamin supplements seem encouraging, overall the results are far from conclusive 
. Certain studies have even raised safety concerns with doses of vitamins C or E far above the recommended dietary intake 
. The meta-analysis published by Jia et al actually concluded that antioxidant supplements in elders aged over 65 years have no beneficial effects on cognitive decline 
. This failure may be partly explained by inadequate amounts or types of antioxidants or inappropriate timing of the supplementation.
Drugs specifically prescribed for memory impairment such as nootropics and vasodilators represent obvious potential interventions to prevent cognitive decline. In France, Ginkgo biloba
extract (EGb761®- Tanakan®) has been marketed for more than thirty years as a medication for memory impairment and is marketed in the United States as a dietary supplement. While the probably most well-known effect of G. biloba
extract is the protection of neuronal cell membranes from free radical damage 
, the properties of EGb761® go beyond that simple antioxidant mechanism. It has been shown to reduce Aβ aggregation and toxicity 
, participate to mitochondrial protection 
and promote hippocampal neurogenesis 
. EGb761® has been also shown to decrease blood viscosity and enhance microperfusion 
. Several studies on rats models also showed that EGb 761® improves neurotransmission, in particular glutamatergic 
, dopaminergic and cholinergic system 
. Therefore, EGb761® can really be considered as a multi-target drug.
Recent reviews and meta-analyses of randomised controlled trials concluded that EGb761® is effective in the treatment of patients with dementia, including Alzheimer's disease, vascular dementia and mixed forms 
, in particular in demented patients with neuropsychiatric symptoms 
. Regarding prevention, only one observational study carried out in a cohort of elderly women has so far suggested the beneficial effect of vasodilators, including G. biloba
, in delaying the onset of dementia 
However, two clinical trials, i.e. the GEM (for Ginkgo Evaluation of Memory) study conducted in 3069 participants aged 75 and over with mild cognitive impairment 
and the GuidAge study conducted in 2854 participants aged 70 and over and reporting memory complaints 
failed to confirm such results. In these studies, G. biloba
at 120 mg twice a day was not effective in reducing the overall incidence of dementia or Alzheimer's disease. However, in both studies, as in another more limited feasibility trial 
, dementia was the main efficacy criteria and the follow-up period was relatively short (3.5 years in Dodge's study ; 6.1 years in the GEM study ; 5 years in the GuidAge study). Due to the particularly long pre-dementia phase of Alzheimer's disease, which is known to progress over decades, expecting a positive effect of G. biloba
on the incidence of dementia over a period of 3 to 6 years would imply that G. biloba
has a direct effect on the neurodegenerative process itself, which is probably an over-optimistic hypothesis. Another alternative interpretation of these negative results might be that G. biloba
is no longer effective once the neurodegenerative process of dementia is too advanced. In this case, dementia outcome over a relatively short follow-up would not be the most relevant outcome to assess the efficacy of G. biloba
on cognitive aging. Therefore, determining whether G. biloba
is associated with long-term cognitive decline may be of interest in order to understand more clearly the usefulness of such treatment in the elderly.
This paper reports the effect of G. biloba on long-term cognitive decline within the PAQUID study. The PAQUID study is a large population-based study conducted in France, which has now 20 years of completed follow-up. As such, it is one of the largest and longest-running prospective studies of the natural history of cognitive decline and the incidence of dementia to have been performed. In this study, the rate of cognitive decline of elderly people reporting use of EGb761® was compared to that of participants reporting use of piracetam, another nootropic agent prescribed for memory impairment in subjects without dementia. Both groups were compared to those participants reporting use of neither of these drugs. The rate of cognitive decline was assessed over a period of 20 years during which cognition has been repeatedly assessed in a standardized manner with three common neuropsychological tests. Due to possible confounding effects of psychotropic drugs on cognitive decline, the association between EGb761® and consumption of psychotropic drugs, including antidepressants, benzodiazepines or antipsychotics, and its possible contribution to the results observed was also considered.