Herbal therapy: a new pathway for the treatment of Alzheimer's disease

It has been a clinical challenge to treat Alzheimer's disease (AD). In the present commentary we discuss whether herbal therapy could be a novel treatment method for AD on the basis of results from clinical trials, and discuss the implications for potential therapy for AD pathophysiology. There is evidence to suggest that single herbs or herbal formulations may offer certain complementary cognitive benefits to the approved drugs. The current evidence supporting their use alone, however, is inconclusive or inadequate owing to many methodological limitations. Herbal mixtures may have advantages with multiple target regulation compared with the single-target antagonist in the view of traditional Chinese medicine. Several clinical trials using herbal mixtures are being conducted in China and will hopefully show promising results for treating AD in the near future.


Introduction
Th e ultimate aim of Alzheimer's disease (AD) therapy is to stop or slow down the disease progression. Cholinesterase inhibitors have a modest clinical eff ect on the symptoms, however, and memantine -the currently available N-methyl-d-aspartate receptor antagonistdoes not prevent the deterioration of dementia [1,2]. Finding an eff ective method to treat AD still poses a signifi cant clinical challenge.
Herbal medicine has long been used in China as therapy for dementia. Th e Complete Work of Jingyue published in 1624 contains the earliest known description in the world of a herbal therapeutic strategy for dementia. In the past 10 years, however, herbal drugs have seldom been approved for use alone in treating dementia.
Overall, systematic review has identifi ed a few single herbs and herbal formulations as possible eff ective medicine for AD (Table 1). According to the current evidence, some of these therapies show promising results in terms of their cognitive benefi ts. In the present commentary we discuss whether herbal therapy could be a novel pathway to treat AD, on the basis of the results from clinical trials, and the implications for potential therapy of AD pathophysiology.

Ginkgo biloba
Ginkgo biloba extract is among the most widely used complementary therapies. A Cochrane review included 36 trials of gingko biloba, but most trials were small and of duration <3 months [3]. Nine trials were of 6 months duration and of adequate size, and were conducted to a reasonable standard. Of the four most recent trials to report results, three studies found no diff erence between Ginkgo biloba, at diff erent doses, and placebo [3], and one study found very large treatment eff ects in favor of Ginkgo biloba, but the trial sample size was very small [4]. Another recent trial reported negative results in reducing cognitive decline in older adults with normal cognition or with mild cognitive impairment [5]. Th e current overall evidence that Ginkgo has a predictable and clinically signifi cant benefi t for people with dementia or cognitive impairment therefore seems inconsistent and unreliable.

Serrate clubmoss
Huperzine A extracted from the serrate clubmoss herb is a potent, reversible and selective inhibitor of acetylcholinesterase. Considering the available evidence from six trials, Huperzine A seems to have some benefi cial eff ects on improvement of general cognitive function, global clinical status, behavioral disturbance and functional performance, with no obvious serious adverse events for patients with AD [6]. Only one study was of adequate quality and size, but the period during this study that found very large treatment eff ects was only 12 weeks [7]. Overall the current evidence supporting clinical use of Huperzine A is presently inconclusive or inadequate.

Abstract
It has been a clinical challenge to treat Alzheimer's disease (AD). In the present commentary we discuss whether herbal therapy could be a novel treatment method for AD on the basis of results from clinical trials, and discuss the implications for potential therapy for AD pathophysiology. There is evidence to suggest that single herbs or herbal formulations may off er certain complementary cognitive benefi ts to the approved drugs. The current evidence supporting their use alone, however, is inconclusive or inadequate owing to many methodological limitations. Herbal mixtures may have advantages with multiple target regulation compared with the single-target antagonist in the view of traditional Chinese medicine. Several clinical trials using herbal mixtures are being conducted in China and will hopefully show promising results for treating AD in the near future.

Ginseng
Panaxi ginseng's main active ingredient is panaxsaponin, which can enhance psychomotor and cognitive performance, and can benefi t AD by improving brain cholinergic function, reducing the level of Aβ and repairing damaged neuronal networks [8]. Th e high-dose ginseng group showed statistically signifi cant improvement on the Alzheimer Disease Assessment Scale (ADAS) and Clinical Dementia Rating (but not on the Mini-Mental State Examination) at the end of the study, when compared with the control group. Th is study was poorly designed, with an insuffi cient description of randomization and without blinding. Furthermore, the sample size was small (n = 15 for each group), and there was also a confounding eff ect due to concurrently administered western medications [9]. Th e evidence for ginseng as a treatment of AD is thus scarce and inconclusive. Further rigorous trials seem warranted [10].

Salvia offi cinalis
Salvia offi cinalis has been used in herbal medicine for many centuries. After 4 months of treatment, salvia offi cinalis extract produced a signifi cantly better outcome on cognitive functions than placebo -as seen on the ADAS cognitive subscale and the Clinical Dementia Rating Sum of Boxes scale in patients with mild to moderate AD aged between 65 and 80 years [11]. Th ere were no signifi cant diff erences between salvia offi cinalis and placebo in terms of the observed side eff ects. In addition, salvia offi cinalis may reduce agitation in patients. More high-quality large-scale randomized controlled trials are needed, however, for further determination of the herb's effi cacy [11].

Herbal formulations or mixtures of herbal ingredients
Herbal formulations or mixtures of herbal ingredients may have advantages with multiple target regulation compared with the single target antagonist in the view of traditional Chinese medicine, although there have been few clinical trials examining the effi cacy and safety of herbal formulations in AD patients.
Shenwu capsule, a mixture of six herbs that is thought to reduce amyloid cytotoxicity, increased the memory score from baseline (n = 83) -but without signifi cant diff erence from aniracetam (n = 83) -in a 12-week phase II trial for patients with mild cognitive impairment [12]. A phase III trial is now underway. Stilbene glycoside, an extract of Shenwu capsule, has been evaluated in a phase I trial for AD. Further results for both of these formulations will be available in the next few years.
GEPT, a combination of fi ve active components extracted from Chinese herbs, may be valuable for the treatment of AD -reducing the level of Aβ via the inhibition of γsecretase (presenilin-1) and the promotion of insulindegrading enzyme and neprilysin, which has been reported in the brain of APPV717I transgenic mice [13]. A 24-week preliminary study of GEPT showed a signifi cant improvement on cognitive function in patients with amnestic mild cognitive impairment, an early stage of AD (n = 101), consistently across diff erent cognitive scales; for example, an improvement in the ADAS cognitive subscale from baseline of -4.19 points (95% confi dence interval = -5.74 to -2.63), which declined at 24 weeks of follow-up after the GEPT withdrawal. Th is level of effi cacy was comparable with that of -4.23 points found in the subjects taking Donepezil (n = 100) ( Figure 1) [14]. GEPT is planned to apply for a shape II trial.
Furthermore, the herbal preparations Ba Wei Di Huang Wan and Yi-Gan San are individually reported to significantly improve cognition or behavior and function on the Mini-Mental State Examination, the Neuro psychi atric Inventory and the Barthel Index in the patients with AD [15,16].

Conclusion
Single herbs or formulations may be able to complement approved drugs for AD. No serious adverse events have been reported. Th e current evidence to support their use alone, however, is inconclusive or inadequate. Th is uncertainty is mainly caused by methodological limitations such as poor study design, relatively small sample sizes without a power calculation, inappropriate outcome measures and primary and secondary end-point selection, and invalid statistical analysis. In addition, the herbs' potential value for prevention and treatment of AD only results from symptomatic changes and short treatment periods (<6 months). Several studies currently underway or in early-stage development in China to evaluate herb mixtures will hopefully show promising results in the near future.
Abbreviations AD, Alzheimer disease; ADAS, Alzheimer Disease Assessment Scale.

Competing interests
The authors declare that they have no competing interests.