|Date: 02-15-2013||HC# 101253-466|
Re: Prolonged Alzheimer’s Disease Prevention Trial Using Ginkgo in Elderly Individuals with Memory Complaints
Vellas B, Coley N, Ousset P-J, et al; for the GuidAge Study Group. Long-term use of standardised Ginkgo biloba extract for the prevention of Alzheimer’s disease (GuidAge): a randomised placebo-controlled trial. Lancet Neurol. 2012;11(10):851-859.
Ginkgo (Ginkgo biloba) extract is used by patients with memory decline associated with aging and Alzheimer’s disease (AD). Observational research suggests that it might help prevent AD. Subjective memory complaints, especially if spontaneously reported to a doctor, are associated with an increased risk of dementia. These patients may have an early stage of mild cognitive impairment and are a target population for interventions aimed at preventing AD. This randomized, double-blind, placebo-controlled, parallel-group, multicenter study, known as the GuidAge study, sought to assess the efficacy of ginkgo in reducing the risk of conversion to AD in elderly individuals spontaneously reporting memory complaints to their primary care physician (PCP).
Participants were recruited throughout France from March 2002 to November 2004, by 712 PCPs belonging to clinical research networks (99%) or by 25 memory centers (1%). All individuals aged ≥ 70 years who lived in the community and consulted 1 of the PCPs or memory centers for memory problems were eligible for screening. Included subjects (n = 2854) had an identified proxy, a mini-mental state examination (MMSE) score of > 25, a Covi anxiety scale score of < 6, and a geriatric depression scale score of < 15. Subjects were excluded for: major objective memory impairment (free and cued selective reminding test [FCSRT] score < 10th percentile for age, sex, and sociocultural level); clinical dementia rating (CDR) of > 0.5; a diagnosis of dementia (according to the Diagnostic and Statistical Manual of Mental Disorders, 4th edition [DSM-IV] and National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer’s Disease and Related Disorders Association [NINCDS-ADRDA] criteria); major depression (DSM-IV criteria); or generalized anxiety (DSM-IV criteria). Participants with mild cognitive impairment were not excluded. Cholinesterase inhibitors were not to be used during the study.
For 5 years, subjects who had been randomly allocated (1:1 ratio) to either the placebo group or the ginkgo group (120 mg of ginkgo extract; EGb 761®; Cara Partners; County Cork, Ireland) were instructed to dose 2x/day. The ginkgo extract was standardized to 24% ginkgo flavone glycosides and 6% terpene lactones (ginkgolides and bilobalide). Treatment adherence was assessed by tablet count. Cognitive, functional, and depressive status were measured every year with the following tests: MMSE, CDR, FCSRT, trail making test, verbal fluency, visual analogue scales, instrumental activities of daily living, and the geriatric depression scale. Safety was assessed every 3 months. The primary efficacy outcome was the incidence of probable AD according to DSM-IV and NINCDS-ADRDA criteria at 5 years.
Treatment compliance appeared to be excellent, with 95% of subjects adhering. For the primary outcome, 61 of 1406 ginkgo-treated subjects were diagnosed with probable AD compared with 73 of 1414 placebo-treated subjects (P = 0.306). The incidence of AD was 1.2 per 100 person-years in the ginkgo group compared with 1.4 per 100 person-years in the placebo group. A total of 70 ginkgo-treated subjects were diagnosed with pure AD or mixed dementia compared with 84 placebo-treated subjects (P = 0.267). Incidence of adverse events was similar in both groups, with no significant difference in the incidence of serious adverse events. Ginkgo treatment did not affect vital signs, physical function, hemorrhagic events, or neurological function. In a prospectively specified subgroup of patients treated for at least 4 years, 15 of 948 subjects treated with ginkgo and 28 of 963 subjects who received placebo developed AD (P = 0.049). This is in line with findings from the observational EPIDOS study, in which the incidence of dementia decreased with increasing time of ginkgo intake.1
The authors conclude that ginkgo did not reduce the incidence of AD. The study is generalizable to elderly patients consulting their physician for memory complaints in a European setting. The 240 mg/day dose of EGb 761 has been shown to be effective in other studies of patients with dementia. GuidAge is the third dementia prevention trial with ginkgo to be completed, and it is the first conducted outside of the USA. The study design was unique in that the study population included people ≥ 70 years of age who were free of dementia at baseline and who had spontaneously reported subjective memory complaints. The main limitation of the study was that the number of dementia events was much lower than expected, leading to a lack of statistical power to detect effects. This could be attributed to the fact that subjects who were screened but refused to participate in the study were older, had lower MMSE scores, and had higher anxiety scores. The authors admit that the effect of long-term exposure to ginkgo warrants additional research due to the low number of dementia events in this trial. It is unfortunate that this well-designed study cannot provide definitive proof of efficacy of ginkgo in the prevention of AD, since delaying its onset for even a few years can greatly reduce the burden caused by this disease.
—Heather S. Oliff, PhD
1Andrieu S, Gillette S, Amouyal K, et al. 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;58(4):372-377.