Chinese Herbal Medicines On Cognitive Function And Activity Of Daily Living in Senior Adults With Alzheimer’s Disease

Contact: joanna.jia@wecistanche.com / WhatsApp: 008618081934791

Yanjie Zhang, et al

Abstract

Background: This systematic review was performed to investigate the effects of Chinese herbal medicine(CHM) on cognitive function and activity of daily living (ADL) in individuals with Alzheimer's disease.Methods: Five electronic databases (Medline, Embase, Cinahl, PsycArticles, and CNKI) were searched from inception to January 2019. Randomized controlled trials (RCTs) assessing the effect of CHM (Chinese herbal medicine) on cognition and activity of daily living in adults with Alzheimer's disease were included. We pooled the size of the effect using the Comprehensive Meta-Analysis software. Cochrane risk of bias tool was used to evaluate the study quality.

Results: Twenty-five RCTs (1855 individuals with AD) were included in this review. Overall findings of this meta-analysis indicated that CHM improved the cognitive function (SMD = 0.66, 95% CI [0.44,0.89], I2 = 77.9%, p < 0.001) and ADL (SMD = 0.38, 95% CI [0.25, 0.49], I2 = 35.3%, p < 0.001) compared with conventional drugs. No publication biases were observed on both cognitive function and ADL.Conclusion: CHM (Chinese herbal medicine) may have potential effects for improving cognitive function and ADL for individuals with AD compared with conventional drug therapies. However, the evidence is limited because of the high risk of bias of the included trials.

Keywords: Alzheimer's disease, Chinese herbal medicine, Cognitive function, Meta-analysis

Chinese herbal medicine-Cistanche has an Anti-Alzheimer's disease function

1. Introduction

Alzheimer's disease (AD), as the most common form of dementia, is a neurodegenerative disorder, and it has multiple symptoms, such as cognitive impairment, activity limitation, depression, and even loss of independence in older adults.1,2 With the aggravated aging problem, a huge number of people are living with AD, which has represented a significant challenge for health issues around the world.3 The World Alzheimer's Disease Report 2016 indicated that a total of 47million populations was diagnosed with dementia, and the estimated number will be increased to 131 million by 2050.4 In today’s the United States, there are approximately 5.7 million adults who are suffering from AD, and one of 10 people aged 65 years and over hasAD according to the national statistic.1 In SouthKorea, the Korean Ministry of Health and Welfare reported that Korean older people with dementia were about 0.5 million in 2012, and the predictable number is expected to increase to 2.7 million by 2050.5

A variety of drugs for the treatment of AD have been applied to the clinic in the past decades. The conventional medicines are commonly aimed at declining theAD progression, such as increasing the level of acetylcholine (Donepezil, Galantamine, and Rivastigmine), an antagonist of the N-methyl-d-aspartate (NMDA) receptor by the Memantine.3 However, a recent meta-analysis study revealed that the Memantine drug had smaller effects on dementia,6 and some conventional medicines contributed to being small effects on cognitive function and ADL for people with AD in long-term treatment.7,8 Additionally, previous studies reported that cholinesterase inhibitors and the Memantine drug have different levels of side effects for patients with AD.9,10 Some patients even stopped taking these drugs.

Chinese herbal medicine (CHM) has been used to protect memory.11 A growing body of evidence suggested that the improvements in cognitive function and ADL in patients with AD may be attributed to the CHM (multi-target intervention effects) to some extent.12–15 Some studies reported that CHM (Chinese herbal medicine) has a similar effect on cognition and activity of daily living (ADL) improvement compared with conventional drug therapy.16,17 Although previous literature review studies18–21 showed several types of CHM (Chinese herbal medicine) may benefit their cognitive function, most of them included several types of dementia together (e.g., vascular dementia, Lewy body dementia) without quantitative analysis.

Therefore, the aim of this study was to investigate whether CHM (Chinese herbal medicine) is more effective than the conventional drug therapies in improving cognitive and ADL deterioration for adults with AD.

2. Methods

2.1. Search strategy

Five electronic databases (Medline, Embase, Cinahl, PsycArticles, and CNKI) were searched for potential publications from their inception to January 2019. We used two groups of search terms to retrieve potentially relevant articles:(1) “Chinese herbal medicine” OR “Chinese herb” OR “traditional Chinese medicine” OR “Chinese medicine”; (2) “Alzheimer's disease” OR “Alzheimer” OR “SenileDementia”. In addition, reference lists of initially retrieved documents were also screened to identify potential publications that were related to our interesting topic. If so, a manual search was performed.

For example, the search strategy was conducted in Medline database:

#1: Chinese herbal medicine

#2: Chinese herb

#3: traditional Chinese medicine

#4: Chinese medicine

#5: #1 OR #2 OR #3 OR #4

#6: Alzheimer's disease

#7: Alzheimer*

#8: #6 OR #7

#9: #5 AND #8

2.2. Inclusion and exclusion criteria

The inclusion criteria were like follows.

2.2.1. Participants

Participants diagnosed with AD according to the Diagnostic and Statistical Manual of Mental Disorders (DSM) III, III-R, or IV were taken into consideration, regardless of gender, age, duration of the disease. We excluded individuals diagnosed with other types of dementia (e.g., vascular dementia, Lewy body disease) or mild cognitive impairment.

2.2.2. Interventions

CHM (Chinese herbal medicine) was defined as a prescription consisting of multiple herbs or patent herbal products. We excluded the combination of CHM (Chinese herbal medicine) with injections or acupuncture.

2.2.3. Control

We included conventional drug therapies (including donepezil, memantine, and galantamine), placebo, or no intervention as control interventions.

2.2.4. Outcomes

The outcome measurements were Mini-Mental State Examination (MMSE) and ADL. We excluded conference proceedings, case-study, cross-sectional studies, controlled studies with no randomization, or review.

2.3. Data extraction

The key information of all eligible studies were independently extracted by two reviewers; author and year of publication, characteristics of subjects, sample size, gender and age, study design, intervention protocol, outcome measurements, and statistical data(mean and standard deviation and the number of participants of each group) needed for computing effect size.

2.4. Risk of bias assessment

The risk of bias of all randomized controlled trials was evaluated according to the Cochrane risk of bias tool.22 This scale involves 7-domain assessment: random sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessment, incomplete outcome data, selective reporting, and other bias.

2.5. Statistical analysis

This meta-analysis was performed using the Comprehensive Meta-Analysis software. As cognition and ADL were measured by different scales across the eligible studies, we used the standardized mean difference (SMD) with a random-effects model with a 95% confidence interval (CI). Three levels of effect size (small [0.2–0.49], medium [0.5–0.79], and large [0.8 or more]) were taken as the corresponding magnitudes of intervention effect. The I2 statistic was employed to assess heterogeneity, and it was classified as 25% (low heterogeneity), 50% (moderate heterogeneity), and 75% (high heterogeneity).23 The Egger's regression test was used to examine the publication bias. In addition, a subgroup meta-analysis was performed based on the type of CHM (Chinese herbal medicine) interventions

Chinese herbal medicine-Cistanche has an Anti-Alzheimer's disease function

3. Results

3.1. Search results

The search and selection process of this review was described based on the PRISMA guideline in Fig. 1. 24 A total of 13,851 records were identified at the initial stage. After removing duplicates (n = 178), the titles and abstracts (n = 13,673) of the remaining articles were screened by two independent reviewers to further determine the eligibility of potential articles; this led to the elimination of 13,596 articles. Seventy-seven full-text articles were further assessed and 53 articles were excluded. Finally, 24 RCT articles regarding the effects of CHM (Chinese herbal medicine) on cognitive function and ADL were included in this review.14–17,25–44

Fig. 1. Flow diagram of the literature search process based on the PRISMA guideline. PRISMA preferred reporting items for systematic reviews and meta-analyses; AD, Alzheimer's disease; MCI, mild cognitive impairment.

3.2. Study characteristics

Details of the included studies are shown in Tables 1 and 2. The studies were published from 2001 to 2018. In total, 1711 participants (mean age from 60 to 84 years) with mild to severe degree of AD were included in this review along with sample size across studies ranging from 20 to 186. The type of CHM (Chinese herbal medicine) treatment varied greatly across the included studies and its intervention duration lasted 2- to 6-month. In the control group where participants were treated with either Donepezil or Piracetam on cognitive function14–17,25–30,32–44 and ADL15–17,25,27,29–34,37–41 were the main outcome measures across the studies included.

3.3. Risk of bias assessment

Details of the quality assessment for each study are presented in Table 3. In terms of random sequence generation, the random number approach was presented in five studies,26,28,31,35, and 18 studies that did not report clearly the random allocation strategies.14–17,26,28–32,34–39,41,44 Two studies were at high risk of bias due to lack of random sequence generation.27,33 In an aspect of allocation concealment, one study reported the allocation concealment,28 and 18 studies did not state the details of allocation concealment.14–17,26–30,32–34,37–41,44 The methods of blinding of participants and personnel were only reported in one study16 the rest of the studies were not described. For blinding of outcome assessment, 23 studies did not provide detailed information,14,15,17,25,27–33,35–45 and only one studies was a low risk of bias.16 The incomplete outcome data was described in all studies. Finally, for the aspect of selective reporting and other bias, no studies reported a clear risk of bias.

3.4. Synthesized results

3.4.1. Cognitive function

A total of 23 studies 14,25–30,32–44 were to investigate the effect of CHM (Chinese herbal medicine) versus conventional drugs in terms of cognitive function, measured by MMSE. The pooled results from 23 studies indicated that CHM (Chinese herbal medicine) had signifificant effect on cognition (SMD = 0.66, 95% CI [0.44, 0.89]) with high heterogeneity (I2 = 77.9%, p < 0.001) in Fig. 2. Of which there were 20 trials 14,25,27–30,32–34,36–44 that assessed the effect of CHM on the cognition compared with Donepezil (SMD = 0.65, 95% CI [0.41, 0.89], I2 = 79.1%, p < 0.001). One study evaluated the effect of CHM on cognition compared with Nimodipine and Sanlexi respectively but there were no statistically signifificant differences between CHM (Chinese herbal medicine) and Nimodipine and Sanlexi.

Fig. 2. Forest plot showing the effect sizes of Chinese herbal medicine on cognitive function compared to conventional drugs. CHM: Chinese herbal medicine. The white circles represent the point of the standardized mean difference. Lines represent 95% confidence intervals. The diamond shows the summary statistic. And p-value <0.05 represents that Chinese medicine is significantly more effective than the control group (conventional drugs) in treating cognition.

3.4.2. ADL

Atotal of 16 studies15–17,25,27,29–34,37–41 compared the CHMwith conventional drug therapies in this meta-analysis. The aggregated results showed improvement in ADL in favor of CHM (SMD = 0.38, 95%CI[0.25, 0.49], I2 = 35.3%, p < 0.001)in Fig. 3. Of which the pooled result from 13 trials indicated that the cognitive improvement was in favor of the CHM (Chinese herbal medicine) compared with the Donepezil (SMD = 0.40, 95% CI[0.22, 0.59], I2 = 46%, p < 0.001). CHM did not have statistically signifificant differences when compared with Nimodipine (SMD = 0.19, 95% CI [−0.51, 0.89], I2 = 0%, p = 0.60), Piracetam (SMD = 0.40, 95% CI [−0.12, 0.91], I2 = 0%, p = 0.13) and Sanlexi (SMD = 0.17, 95% CI [−0.33, 0.67], I2 = 0%, p = 0.50).

Fig. 3. Forest plot showing the effect sizes of Chinese herbal medicine on the activity of daily living compared to conventional drugs. CHM: Chinese herbal medicine. The white circles represent the point of the standardized mean difference. Lines represent 95% confidence intervals. The diamond shows the summary statistic. And p-value <0.05 represents that Chinese medicine is significantly more effective than the control group (conventional drugs) in treating activity of daily living.

3.5. Publication bias

The result of Egger’s test represented no statistically signifificant publication bias (p = 0.31). In terms of ADL performance, the result of Egger’s test revealed no statistically signifificant publication bias (p = 0.64).

Chinese herbal medicine-Cistanche has an Anti-Alzheimer's disease function

4. Discussion

We conducted a systematic review and meta-analysis to evaluate the efficacy of CHM (Chinese herbal medicine) on cognition and ADL in patients with AD. Our findings indicated that the CHM may enhance cognitive function and ADL compared with conventional drug therapy, at least as effective as other drugs. However, the overall risk of bias prevents the firm conclusion. The results need to be interpreted with caution, especially for practitioners who recommend prescriptions to patients.

Pooled analysis indicated that after taking CHM (Chinese herbal medicine), AD patients can improve their abilities in terms of cognition and activity with sigsignificant effects. Although several studies failed to show the superior effects of CHM (Chinese herbal medicine) on cognitive function and ADL compared with conventional drugs, these results may be interpreted as the equivalent effects of CHM (Chinese herbal medicine) with conventional drug therapies.15,17,20,36,46 In the Chinese medical theories, the multi-herbs of CHM may have synergetic effects on regulating the Amyloid-beta and calcium disorder, as accumulating Amyloid-beta and calcium disorder are associated with the physiology pathology of AD.47–49 For example, CHM (i.e., Yizhi formula) can reduce the A aggregation and calcium ion activity, and further improve the memory abilities in A-induced mice.50,51 Not only does CHM regulate immune-neuroendocrine functions and hemorheology but also altered cognitive dysfunction.52 Taken together, the CHMs seem to have great benefits to the relief of patients with AD though changing or regulating signaling pathways (e.g., calcium, enzyme), neuroregeneration, and even reducing A concentration.53,54

We would like to acknowledge several limitations in this current review study. First, although the present systematic review and meta-analysis were not registered in PROSPERO, we tried to avoid bias in the post hoc analysis. Second, there are several intrinsic caveats in the primary studies and they may affect the quality of this study. Third, the original authors did use proper sample size calculation, and this may underestimate the efficacy of the intervention. Fourth, we did not perform meta-regression to find the cause of heterogeneities and this may exaggerate the effects of the treatment. Finally, the prescription and doses of CHMs were vary according to the studies and these may occur the heterogeneity of meta-analysis.

In conclusion, the results of this systematic review suggest that CHM (Chinese herbal medicine) treatment may have potential effects on improving cognitive function and ADL for individuals with AD. However, the evidence is limited because of the high risk of bias of included studies. Further rigorous studies are needed to confirm the efficacy.

Chinese herbal medicine-Cistanche has an Anti-Alzheimer's disease function

References
1. Alzheimer’s Association. 2018 Alzheimer's disease facts and figures. Alzheimer’s Dement 2018;14:367–429.
2. Ahn N, Kim K. Effects of an elastic band resistance exercise program on lower extremity muscle strength and gait ability in patients with Alzheimer's disease. J Phys Ther Sci 2015;27:1953–5.
3. Noetzli M, Eap CB. Pharmacodynamic, pharmacokinetic, and pharmacogenetic aspects of drugs used in the treatment of Alzheimer's disease. Clin Pharmacokinet 2013;52:225–41.

4. Prince M, Comas-Herrera A, Knapp M, Guerchet M, Karagiannidou M. World Alzheimer Report 2016 improving healthcare for people living with dementia. Coverage, Quality, and costs now and in the future. Alzheimer’s Dis Int 2016:1–140,

5. Number of dementia patients to surpass 2.7 million by 2050. BOOK IT. Accessed July 20, 2018.

6. Knight R, Khondoker M, Magill N, Stewart R, Landau S. A systematic review and meta-analysis of the effectiveness of acetylcholinesterase inhibitors and memantine in treating the cognitive symptoms of dementia. Dement Geriatr Cogn Disord 2018;45:131–51.
7. Ströhle A, Schmidt DK, Schultz F, Fricke N, Staden T, Hellweg R, et al. Drug and exercise treatment of Alzheimer's disease and mild cognitive impairment: a systematic review and meta-analysis of effects on cognition in randomized controlled trials. Am J Geriatr Psychiatry 2015;23:1234–49
8. Raina P, Santaguida P, Ismaila A, Patterson C, Cowan D, Levine M, et al. Effectiveness of cholinesterase inhibitors and memantine for treating dementia: evidence review for a clinical practice guideline. Ann Intern Med 2008;148:379–97
9. Landi F, Russo A, Liperoti R, Cesari M, Barillaro C, Pahor M, et al. Anticholinergic drugs and physical function among the frail elderly population. Clin Pharmacol Ther 2007;81:235–41.
10. Zhou J, Peng W, Xu M, Li W, Liu Z. The effectiveness and safety of acupuncture for patients with Alzheimer's disease. Medicine (Baltimore) 2015;94:e933
11. Chen X. Shen Nong Ben Cao Jing. Beijing: China Academy Press; 2011:60–80.
12. Bi M, Tong S, Zhang Z, Ma Q, Zhang S, Luo Z, et al. Changes in cerebral glucose metabolism in patients with mild-to-moderate Alzheimer's disease: a pilot study with the Chinese herbal medicine fuzhisan. Neurosci Lett 2011;501:35–40, http://dx.doi.org/10.1016/j.neulet.2011.06.036.
13. Zhang Y, Lin C, Zhang L, Cui Y, Gu Y, Guo J, et al. Cognitive improvement during treatment for mild Alzheimer's disease with a Chinese herbal formula: a randomized controlled trial. PLoS One 2015;10:e0130353.
1371/journal.pone.0130353.
14. Zhang L, Peng J. Qingxin Yizhi decoction on improving the quality of life, cognitive level, and the biochemical indexes of SOD and MDA in AD patient. Shanxi J Tradit Chinese Med 2018;39:593–5.
15. Liu P, Kong M, Liu S, Chen G, Wang P. Effect of reinforcing kidney-essence, removing phlegm, and promoting mental therapy on treating Alzheimer's disease. J Tradit Chinese Med 2013;33:449–54
16. Wang S. Clinical effect of Congrong Yizhi decoction on people with Alzheimer's Disease. Zhejiang J Chinese Med 2015;50:386–7. cnki.zjtcm.2015.05.062.17. Yang P, Dong K. Clinical Effects of Yizhi Jiannao granule on Alzheimer’ Disease.
J New Chinese Med 2013;45:56–8.
18. May BH, Lit M, Xue CCL, Yang AW, Zhang AL, Owens MD, et al. Herbal medicine for dementia: a systematic review. Phytother Res 2009;23:447–59.
19. Fu L-M, Li J-T. A systematic review of single Chinese herbs for Alzheimer's disease treatment. Evid Based Complement Alternat Med 2011 2011:640284.

20. Santos-Neto LL, de Vilhena Toledo MA, Medeiros-Souza P, de Souza GA. The use of herbal medicine in Alzheimer's disease—a systematic review. EvidenceBased Complement Altern Med 2006;3:441–5.

21. Hyde AJ, May BH, Dong L, Feng M, Liu S, Guo X, et al. Herbal medicine for the management of the behavioral and psychological symptoms of dementia (BPSD): a systematic review and meta-analysis. J Psychopharmacol 2017;31:169–83.
22. Higgins JPT. Cochrane Handbook for systematic reviews of interventions version. The Cochrane Collaboration; 2011:2–3.
23. Higgins JPT, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ Br Med J 2003;327:557–60.
24. Moher D, Liberati A, Tetzlaff J, Altman DG. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med 2009;6:e1000097.
25. Ding X, Zang Q, Sun Q, Zhang J. Clinical research of Shenghuangyizhi granule on Alzheimer's disease. Chinese J Gerontol 2009;29:2023–4, 25.
26. Li Z, Mu Y, Ouyang Q. Clinic control research of Alzheimer's disease by the combination of acupuncture and Danggui Shaoyao San (DGSYS) of TCM. Chinese J Clin Rehabil 2002;6:2848–9.
27. Jia X, Luo H, Xu W, Miao Y. Observation on the efficacy of Rehmanniae decoction in the modified treatment of Alzheimer's. Eval Anal drug-use Hosp China 2018;18:499–501.
28. Jin X, Duan Y, Zhang D, Liu Z, Mei Q, Huang H, et al. Observation on the effect of tong Qiao huo xue decoction on Alzheimer's disease. Chinese J Integr Med Cardio- /Cerebrovascular Dis 2017;15:15–7.
29. Wang E. Clinical observation on 20 cases of Alzheimer's disease treated by Jiaweizuoguiwan. Jiangsu Tradit Chinese Med 2013;45:38–9.
30. Fu K, Lin C, Zhang Y, Guo J, Wang X, Cui Y. Clinical study on treatment of 15 cases of mild Alzheimer's disease with Yishenhuazhuofang. Jiangsu Tradit Chinese Med 2012;44:28–9.
31. Zhou R, Lin S, Wang J, Yu Z. Clinical study on life ability improved by “KidneyTonifying Formula” in Alzheimer's disease. Mod Rehabil 2001;5:35–8.
32. Zhu H, Dong K, Wu Y, Zhang T, Li R, Hu S, et al. Effect of Bushenhuoxue method on cognitive function improvement of Alzheimer's disease patients. Chinese J Gerontol 2010;30:1493–5.
33. He H, Zhou R. Revised Buyang Huanwu decoction treat senile dementia (SD) 35 cases. Zhejiang Chinese Med Univ 2013;37:723–4.
34. Zhou Z, Liang L, Yan Y. Clinical study of Reinhardt and sea cucumber capsule combined with donepezil in treating Alzheimer's disease. Chinese J Integr Tradit West Med 2007;21:110–3.
35. Gao P, Wen S, Qin S, Cai X. A clinical study of the efficacy and safety of Fufanghaishe capsule in the treatment of Alzheimer's disease. Chinese J Clin Healthc 2004;7:401–2.
36. Chang F, Yuan Y, Sun Y, Lai J, Song X, Lin Y, et al. Clinical research on refined Xingnao power in the treatment of senile dementia. Chinese Arch Tradit Chinese Med 2013;30:1253–5.
37. Li X, He M. Effect of Naoling decoction on MMSE and serum pro-inflammatory cytokines in patients with Alzheimer's disease. Pract Prev Med 2010;17: 959–61.
38. Lin S, Zhou R, Wang J, Yu Z. Comparative study of “heart-regulating formula” and “kidney-tonifying formula” in treating the cognition and daily life ability of Alzheimer's disease. Chinese J Gerontol 2002;22:434–6.

39. Wang J. A clinical study on the treatment of Alzheimer's disease with Diaoxinfang. J Beijing Univ Tradit Chinese Med 2002;25:51–3.

40. Chen W, Jiang L, Liu T, Gu L, Wu P, Wang J, et al. Clinical observation on 40 cases of senile dementia with phlegm resistant obstruction syndrome treated by Wenpitongluokaiqiao decoction. J Tradit Chinese Med 2013;54:1759–61.
41. Liu P, Dong K. Effect of Yizhijiannao granule on the expression of IL-1 and TNF-α in peripheral serum of patients with Alzheimer's disease. Hunan J Tradit Chinese Med 2010;26:1–3.
42. Zhang F. Treatment of 38 cases of Alzheimer's disease with Yizhi decoction. J Chinese Med 2009;24:45–6.
43. Peng XW, Dong KL. Clinical observation on acupuncture combined with Yizhi Jiannao granules for treatment of Alzheimer's disease. Chinese Acupunct Moxibust 2009;29:269–71.
44. Yan S, Yan S, Qi D, Niu Y, Wang M. Clinical observation on 93 cases of Alzheimer's disease treated by Zhijing oral liquid. Guangxi Tradit Chinese Med 2007;30: 30–2.
45. May BH, Lu C, Lu Y, Zhang AL, Xue CCL. Chinese herbs for memory disorders: a review and systematic analysis of classical herbal literature. JAMS J Acupunct Meridian Stud 2013;6:2–11, http://dx.doi.org/10.1016/j.jams.2012.11.009.
46. May BH, Feng M, Hyde AJ, Hügel H, Chang S, Dong L, et al. Comparisons between traditional medicines and pharmacotherapies for Alzheimer's disease: a systematic review and meta-analysis of cognitive outcomes. Int J Geriatr Psychiatry 2018;33:449– 8.
47. Yang H, Wen SR, Zhang GW, Wang TG, Hu FX, Li XL, et al. Effects of Chinese herbal medicine Fuzhisan on autologous neural stem cells in the brain of SAMP- 8 mice. Exp Gerontol 2011;46:628–36.
48. Fu X, Wang Q, Wang Z, Kuang H, Jiang P. Danggui-Shaoyao-San: new hope for Alzheimer's disease. Aging Dis 2016;7:502–13.

49. Lin Z, Xiao Z, Zhu D, Yan Y, Yu B, Wang Q. Aqueous extracts of FBD, a Chinese herb formula composed of Poria cocos, Atractylodes macrocephala, and Angelica Sinensis reverse scopolamine-induced memory deficit in ICR mice. Pharm Biol 2009;47:396–401.

50. Cai H, Luo Y, Yan X, Ding P, Huang Y, Fang S, et al. The mechanisms of bushen-yi zhi formula as a therapeutic agent against Alzheimer's disease. Sci Rep 2018;8:3104, .

51. Woods NK, Padmanabhan J. Neuronal calcium signaling and Alzheimer's disease. Advances in experimental medicine and biology. vol. 740. Dordrecht: Springer; 2012:1193–217.
52. Kou J, Zhu D, Yan Y. Neuroprotective effects of the aqueous extract of the Chinese medicine Danggui-Shaoyao-san on aged mice. J Ethnopharmacol 2005;97:313–8.
53. Sreenivasmurthy S, Liu J-Y, Song J-X, Yang C-B, Malampati S, Wang Z-Y, et al. Neurogenic traditional Chinese medicine as a promising strategy for the treatment of Alzheimer's disease. Int J Mol Sci 2017;18:272.
54. Wang Z-Y, Liu J-G, Li H, Yang H-M. Pharmacological effects of active components of Chinese herbal medicine in the treatment of Alzheimer's disease: a review. Am J Chin Med 2016;44:1525–4.1