The Effectiveness of Acupuncture Treatment for Patients with Alzheimer’s Disease: A Meta-Analysis of Randomized Controlled Trials

Jin Hyeon Shin; Hye Jeong Shin; Eui Byeol Kim; Yun Young An; Tae Han Yook; Yoo Min Choi; Beom Yong Song; Jong Uk Kim

doi:10.13045/jar.2020.00255

J Acupunct Res > Volume 37(4); 2020 > Article

Shin, Shin, Kim, An, Yook, Choi, Song, and Kim: The Effectiveness of Acupuncture Treatment for Patients with Alzheimer’s Disease: A Meta-Analysis of Randomized Controlled Trials

Review Article

Journal of Acupuncture Research 2020; 37(4): 209-223.

Published online: November 23, 2020

DOI: https://doi.org/10.13045/jar.2020.00255

The Effectiveness of Acupuncture Treatment for Patients with Alzheimer’s Disease: A Meta-Analysis of Randomized Controlled Trials

Jin Hyeon Shin¹

, Hye Jeong Shin¹

, Eui Byeol Kim²

, Yun Young An³

, Tae Han Yook¹

, Yoo Min Choi¹

, Beom Yong Song¹

, Jong Uk Kim^1,^*

¹Department of Acupuncture and Moxibustion Medicine, Korean Medicine Hospital of Woosuk University, Jeonju, Korea

²Department of Rehabilitation Medicine of Korean Medicine, Korean Medicine Hospital of Woosuk University, Jeonju, Korea

³Department of Neuropsychiatry, College of Korean Medicine, Woosuk University, Jeonju, Korea

^*Corresponding author: Jong Uk Kim, Department of Acupuncture and Moxibustion Medicine, Korean Medicine Hospital of Woosuk University, Jeonju, Korea, E-mail: ju1110@hanmail.net

Received July 27, 2020 Revised October 07, 2020 Accepted October 23, 2020

This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Abstract

The purpose of this study was to evaluate the effectiveness of acupuncture treatment for the symptoms of Alzheimer’s disease (AD). There were 11 databases searched for randomized controlled trials using acupuncture treatment for AD. The risk-of-bias assessment tool of the Cochrane Library was used to evaluate the quality of each study. Using the Review Manager (RevMan), a meta-analysis was performed using risk ratio, mean difference, 95% confidence interval, and random effect model. There were 32 studies selected, all of which were conducted in China. There were 16 studies where acupuncture was used as the intervention, and 23 studies used Donepezil as the control group. Acupoint GV20 was most frequently selected during the treatment. The Mini Mental State Examination (MMSE) was the most frequently used outcome variable. A period of 12 weeks was the most common treatment duration. As a result of meta-analysis (n = 25), acupuncture improved the MMSE and activities of daily living scores. Electroacupuncture improved the Alzheimer Disease Assessment Scale-Cognitive Subscale, and scalp acupuncture improved the MMSE score for AD. Acupuncture alleviates the symptoms of AD. However, further research is necessary to provide a better level of evidence.

Key Words: Alzheimer disease; acupuncture; cognition disorders; activities of daily living; meta-analysis.

Introduction

Dementia is a syndrome comprehensively referring to the decline in cognitive functions like memory, orientation, daily life problems, insensitivity, depression, anxiety, delusions, hallucinations, and wandering, and behavioral and psychological symptoms of dementia (BPSD). There are various stages of dementia, and Alzheimer disease (AD) is the most common cause (55–70% of all dementia patients) [1]. Other common causes include vascular dementia, Lewy body dementia, and frontotemporal lobar degeneration.

AD is characterized by the progressive damage of cognitive function, and in about 80% of all patients, BPSD appear which may cause deterioration in the patients quality of life and cause suffering for patient and their caregivers [2].

The prevalence rate of dementia in Korea in the population aged 65 years and over has gradually increased from 9.54% in 2015, to 10.29% in 2019, and in particular, the ratio of AD amounts to about 70% of all cases of dementia. In the total elderly population, AD has a high prevalence rate (7%). Medical care benefit costs for dementia amounted to 1.29 trillion won in 2015, and 1.95 trillion won in 2019, which causes a huge social economic burden [3].

At present, there are no treatments for AD just treatments for temporarily alleviating or delaying symptoms e.g. drug therapy like acetylcholinesterase inhibitors (e.g. Donepezil) and glutamate receptor antagonist (e.g. Memantine), and therapies and activities (e.g. cognitive rehabilitation with occupational therapy, cognitive stimulation such as art therapy, music therapy, or exercise therapy, and reminiscence therapy) [4].

Korean medicine treats AD using reminiscence therapy, cognitive function training mixed with Korean medicine treatment (such as acupuncture, moxibustion, and herbal medicine [5]). Various studies have been conducted to verify the effect of Korean medicine treatment on AD. In the published studies of herbal medicine treatment for AD, case reports and the assessments of the effects of oriental medicine have been published [6,7], while in the studies of acupuncture treatment of AD, case reports and studies of acupuncture with magnetic resonance imaging scans have been published [8,9]. In addition, meta-analysis studies of the effect of acupuncture were also reported [10–12]. However, most of the existing meta-analysis studies did not reflect the latest data since they included studies conducted before 2017, and did not reflect the treatment of AD in Korea [10–12]. Thus, the studies conducted in Korea and internationally until June 2020, were included in this literature review to assess the effect of acupuncture on the improvement of symptoms of AD.

Materials and Methods

Search Strategy

Korean databases [National Digital Science Library (NDSL), Korean studies Information Service System (KISS), Research Information Sharing Service (RISS), KoreaMed, Korean Medical dataBASE (KMBASE), and OASIS], and international databases [PubMed, Excerpta Medica dataBASE (EMBASE), Cochrane Central Register of Controlled Trials (CENTRAL), China Academic Journal (CAJ), and Scholarly and Academic Information Navigator (CiNii)] were used to retrieve articles before June 15^th, 2020.

The core search was based on the Medical Subject Headings (MeSH) of the National Library of Medicine. The patient group was only patients with AD and the intervention was only acupuncture. There were no restrictions placed on the publication year, language, or country of study. Titles and abstracts were searched using MeSH terms according to each academic database (Table 1).

Criteria for selection and exclusion

Selection criteria

Patients in studies who were diagnosed with AD based on diagnostic criteria as described in The Diagnostic and Statistical Manual of Mental Disorders (DSM) [2], National Institute of Neurological and Communicative Disorders and Stroke and the AD and Related Disorders Association (NINCDS-ADRDA) [13,14], National Institute of Aging and Alzheimer Association (NIA-AA) [15], or International Classification of Diseases (ICD) [16] were included in this review.

Acupuncture treatment for AD that was part of a clinical study or a randomized controlled trial which verified the effectiveness of the acupuncture treatment (without restrictions placed upon the intervention or the control group).

Exclusion criteria

Studies that were unable to verify the effectiveness of the acupuncture treatment for AD, used human cell culture or animal models, was a literature review, a case report, or an observational study, and a study for which the full text was not accessible.

Measurement tools for the outcome variable

The Mini Mental State Examination (MMSE) and the Alzheimer’s Disease Assessment Scale-Cognitive Subscale (ADAS-cog) were used to assess cognitive function. Activities of Daily Living (ADL) was used to assess the activities in daily life. Dementia Neuro-Psychiatric Inventory (NPI) was used to assess BPSD, and the effective rate (the ratio of people who showed treatment effect to the number of subjects in each group) was used to measure the outcome variable [17].

Data extraction

Study selection

One researcher searched for articles based on the inclusion criteria, and another reviewed the results. The title and abstract were checked in the first screening process, and the full text was checked in the second screening. If necessary, the selection of an article was in agreement between the researchers. If the data were incomplete, the authors were contacted using the corresponding author email address on the publication, and if communication was not possible, the study was excluded.

Data extraction

One researcher extracted information from each study and prepared a summary table of demographic information, intervention, treatment duration, outcome variables, and side effects of the 32 included studies. Another researcher reviewed that process.

Risk-of-bias assessment

There were 2 independent researchers who assessed the risk of bias (RoB), using the Revised Cochrane RoB tool for randomized trials. If the assessments by each researcher were different, the RoB was decided by agreement between the 2 researchers.

Meta-analysis method

The therapeutic effect was assessed using 2 or more studies in the Review Manager (RevMan) Version 5.4.0 (Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2014). Analysis was performed using risk ratio (RR) as a dichotomous variable and mean difference (MD) as a continuous variable. A random-effect model with a 95% confidence interval (CI) was used for the meta-analysis. The heterogeneity between studies was evaluated, using the Chi-square test and Higgin’s I² statistics (I²), an I² of more than 50% indicated heterogeneity between the studies. If heterogeneity was confirmed, neither subgroup analysis nor meta-regression was performed.

Publication bias assessment

When there were more than 10 studies with matching intervention and outcome variables, publication bias was assessed using the funnel plot in RevMan.

Results

Search results

There were 2,192 studies initially retrieved from the selected databases. There were 60 articles retrieved from previously published meta-analysis studies resulting in a total of 2,252 studies. Excluding 999 duplicate articles the first screening resulted in 1,253 articles. The full texts were checked in the second screening where the criteria for selection and exclusion were used. There were 32 studies included in this review. The process of selecting the articles is shown in the PRISMA flow chart (Fig. 1), and the summary of study selection is described in Table 2.

Characteristics of the selected studies

Year and country of publication

Of the 32 included studies, 1 was published before 2000; 5, between 2000 and 2010; and 26, after 2010. There was 1 study published in 1999; 1, in 2002; 1, in 2007; 1, in 2008; 1, in 2009; 1, in 2010; 1, in 2013; 10 in 2014; 3, in 2015; 1, in 2016; 2, in 2017; 5, in 2018; 2, in 2019; and 2, in 2020. All studies were conducted in China. There were 3 studies written in English, and 29 studies written in Chinese.

Sample size

There were 2,210 patients across the 32 randomized controlled trials, of which 35 patients dropped out of 4 studies, 2,175 patients remained. The minimum sample size was 30, and the maximum was 141. The number of patients in the intervention group was between 15 and 72, and there were between 14 and 69 in the control group.

Evaluation of results

The duration of treatment in each study was between 20 and 180 days. There were 7 studies which treated patients for 8 weeks; 4, for 4 weeks; and 3, for 3 months. There were 8 which had various treatment periods between 20 and 180 days. As for evaluation indices, the MMSE was used in 27 out of the 32 studies. The effective rate was used in 22 studies. ADL was used in 16 studies; ADAS-cog, in 8 studies; and NPI, in only 1 study [39]. In most studies, the evaluation was performed before and after the treatment, and in 1 study, an intermediate evaluation was performed at Week 6 of the 12-week treatment period [24]. Of all the studies, 3 studies had a follow-up period, which was 12 weeks after the treatment [29,39,46].

Intervention

A total of 16 studies used acupuncture treatment as an intervention. Of those, 9 studies used acupuncture alone. There were 3 studies that used herbal medicine in combination with acupuncture; 3, Western medicine and 1, a placebo [42]. There were There were10 studies that performed electroacupuncture treatment. There were 6 studies that used electroacupuncture alone; 2, herbal medicine in combination with electroacupuncture; and 2, Western medicine. There were 4 studies that used scalp acupuncture, and no electrical stimulation was used in parallel. Of those, 3 studies used Western medicine in combination with scalp acupuncture, and 1 study used scalp acupuncture alone. There was 1 study that used warm needle acupuncture and 1 study that used fire needle acupuncture. Both studies used acupuncture and Western medicine as the intervention.

Control group

As for the number of control groups, 29 studies used 1 control group, and 3 studies used 3 control groups [19,23,36]. There were 29 studies that used Western medicine as the control group. Of those, 23 studies used Donepezil; 3, Nimodipine; 1, Almitrine and Raubasine complex; 1, Huperzine A; and 1, used a placebo. There was a total of 6 studies that used herbal medicine as the control group. The control group for each type of intervention group was as follows. The intervention group that used acupuncture treatment used Nimodipine in 1 case; Donepezil, in 12; Almitrine and Raubasine complex, in 1; Korean medicine, in 3; placebo, in 1 as the control group. The intervention group that used electroacupuncture treatment used Donepezil in 6 cases; Nimodipine, in 2; Huperzine A, in 1; and Korean medicine, in 2 as the control group. The intervention group that used scalp acupuncture treatment used Donepezil in 3 cases and herbal medicine in 1 case as the control group. The intervention group where warm and fire needle acupuncture was used, Donepezil was the control group.

Acupoints

In 32 studies, a total of 73 acupoints were used 218 times. There were 16 scalp acupoints used in 4 studies. There was 1 study that used eye acupuncture in addition to acupuncture, so 4 additional eye acupoints were included [22]. Throughout all studies, GV20 was used the most (in 24 studies). ST36 was also used (in 12 studies); and EX-HN1 (in 10 studies). For acupuncture intervention, GV20, ST36, GB39, LR3, EX-HN3 were mostly used. In 10 studies that used electroacupuncture, GV20 was used the most (in 7 studies). GV14, GV16, GV24 were also used (in 3 studies; Table 3).

Adverse events

Of 32 studies, 5 studies mentioned that adverse events had occurred in the study. Li et al [27] reported that no adverse events occurred in the study. Gu et al [26] reported bleeding and pain in the acupuncture intervention group, there was 1 case of gastrointestinal disorder, and 8 cases of loss of appetite, nausea, diarrhea, and insomnia in the Donepezil control group. Feng et al [46] reported pain in 2 patients who underwent acupuncture treatment and a local hematoma in 1 patient. Zhang et al [47] reported 2 cases of nausea and vomiting in the group using fire needle acupuncture and Donepezil. They also reported 2 cases of diarrhea, 5 cases of nausea, and 1 case of insomnia in the Donepezil monotherapy group. Jia et al [39] reported that a condition not related to AD improved after acupuncture treatment, including 5 cases of insomnia, 4 cases of constipation, 6 cases of benign prostatic hyperplasia, and 2 cases of knee joint disease.

RoB assessment

Random sequence generation

In 2 studies, the RoB was high because patients were assigned to a group according to the sequence of visits and treatments in random allocation [22,28]. Nine studies were judged to have an unclear RoB since they did not mention the method of random allocation. In the remaining 21 studies, the RoB was low because patients were randomly allocated using the tables of random numbers or drawing lots.

Allocation concealment

In 4 studies, the allocation sequence was concealed, using a sealed envelope [39,46,48,49]. The other 28 studies did not mention allocation concealment.

Blinding of the study to participants and personnel

Although all 32 studies did not mention blinding, it was judged that the blinding of the study to participants and personnel was not performed due to the nature of the intervention since all studies compared acupuncture treatment with herbal medicine or Western medicine. Thus, the RoB in all studies was judged to be high.

Blinding of outcome assessment

The RoB in only 2 studies was judged to be low due to blinding of the study to the assessor [39,46], the remaining 30 studies were judged to be unclear because it was not mentioned.

Incomplete outcome data

The RoB of 1 study was judged as unclear because the total number of patients or the number of dropouts was not mentioned in the outcome variables [24]. The RoB of the remaining 31 studies was judged to be low because the occurrence of dropouts or the inclusion of statistics of the dropouts was mentioned, or the study was completed without dropouts.

Selective reporting

RoB for selective reporting were unclear in all 32 studies.

Other bias

In all 32 studies, it was unclear whether there were other biases (Figs. 2 and 3).

Effectiveness evaluation

Of 32 studies, 7 studies were excluded because they did not use the same intervention and outcome variables. Therefore, a total of 25 studies were used for meta-analysis.

Acupuncture versus Donepezil

In 7 studies, acupuncture treatment intervention groups had statistically significantly improved the MMSE scores in AD patients compared with Donepezil [MD = 1.57, 95% CI (0.29, 2.86), I² = 88%, Z = 2.40, p = 0.02]. Acupuncture significantly improved ADL scores in 5 studies [MD = −2.22, 95% CI (−2.81, −1.62), I² = 0%, Z = 7.29, p < 0.00001] and the effective rate in 6 studies [RR = 1.42, 95% CI (1.20, 1.67), I² = 17%, Z = 4.12, p < 0.0001]. In 2 studies which compared the acupuncture treatment intervention group with Donepezil, acupuncture treatment did not show a significant improvement in ADAS-cog scores [MD = −1.49, 95% CI (−4.64, 1.65), I² = 0%, Z = 0.93, p = 0.35]. For BPSD, there was 1 study that compared acupuncture with Donepezil, but it did not show any statistically significant differences [MD = −0.36, 95% CI (−1.46, 0.74), Z = 0.64, p = 0.52; Fig. 4].

Acupuncture plus Donepezil versus Donepezil

In 3 studies that compared acupuncture and Donepezil combined treatment intervention group with Donepezil monotherapy, acupuncture significantly improved the ADL scores [MD = −3.12, 95% CI (−4.56, −1.69), I² = 61%, Z = 4.25, p < 0.0001]. There were no statistically significant differences in 3 studies that compared the acupuncture and Donepezil combined treatment intervention group with the Donepezil monotherapy using the MMSE score [MD = −0.04, 95% CI (−2.88, 2.79), I² = 97%, Z = 0.03, p = 0.98]. For ADAS-cog score [MD = −1.57, 95% CI (−4.37, 1.24), I² = 79%, Z = 1.10, p = 0.27] and effective rate [RR = 1.72, 95% CI (0.75, 3.97), I² = 72%, Z = 1.27, p = 0.20], and when the acupuncture and Donepezil combined treatment intervention group was compared with Donepezil monotherapy, it did not show statistically significant differences (Fig. 5).

Acupuncture versus herbal medicine

There were 2 studies that compared acupuncture with herbal medicine which did not show statistically significant differences in effective rate [RR = 1.01, 95% CI (0.81, 1.28), I² = 0%, Z = 0.12, p = 0.90; Fig. 6A].

Acupuncture plus herbal medicine versus herbal medicine

There was no significant difference in the comparison of acupuncture and herbal combined treatment intervention group with herbal treatment alone in the effective rate [RR = 1.14, 95% CI (0.93, 1.39), I² = 0%, Z = 1.29, p = 0.20; Fig. 6B].

Electroacupuncture versus Western medicine

There were no statistically significant differences in the 4 studies that compared electroacupuncture intervention treatment with Donepezil using the MMSE score [MD = 1.35, 95% CI (−0.01, 2.72), I² = 55%, Z = 1.94, p = 0.05]. Electroacupuncture did not show statistically significant differences compared to Nimodipine in ADL scores [MD = 2.53, 95% CI (−1.70, 6.77), I² = 91%, Z = 1.17, p = 0.24]. In the comparison between electroacupuncture and Nimodipine [RR = 0.76, 95% CI (0.53, 1.08), I² = 0%, Z = 1.52, p = 0.13] and the comparison between electroacupuncture and Donepezil [RR = 1.17, 95% CI (0.98, 1.39), I² = 0%, Z = 1.78, p = 0.08], there were no significant differences (Fig. 7A).

Electroacupuncture plus Donepezil versus Donepezil

In ADAS-cog score, 2 studies that compared the improvement between the electroacupuncture and Donepezil combined treatment intervention group, with the Donepezil group, the electroacupuncture group showed a significant improvement [MD = −3.36, 95% CI (−5.18, −1.54), I² = 0%, Z = 3.62, p = 0.0003; Fig. 7B].

Electroacupuncture plus herbal medicine versus herbal medicine

In a comparison of electroacupuncture and herbal medicine combined treatment intervention and herbal medicine monotherapy, the improvement of electroacupuncture on the effective rate showed a statistically significant difference [RR = 1.35, 95% CI (1.09, 1.68), I² = 0%, Z = 2.75, p = 0.006]. There were no statistically significant differences in 2 studies that compared the electroacupuncture and herbal medicine combined treatment intervention group, with the herbal medicine monotherapy group using the MMSE score [MD = 5.16, 95% CI (−0.62, 10.94), I² = 96%, Z=1.75, p = 0.08] and the ADL scores [MD = −5.80, 95% CI (−13.42, 1.82), I² = 90%, Z = 1.49, p = 0.14; Fig. 8].

Scalp acupuncture plus Donepezil versus Donepezil

In 3 studies that compared the scalp acupuncture and Donepezil combined treatment intervention group with the Donepezil monotherapy group, the effect of acupuncture on the improvement of the MMSE score was statistically significant [MD = 1.81, 95% CI (0.13, 3.49), I² = 0%, Z = 2.11, p = 0.03]. There were no statistically significant differences between the comparison of scalp acupuncture and Donepezil combined treatment intervention group, with Donepezil alone using the ADL score [MD = −2.02, 95% CI (−4.72, 0.67), I² = 66%, Z = 1.47, p = 0.14; Fig. 9].

Warm acupuncture plus Donepezil versus Donepezil

In 1 study, the warm acupuncture and Donepezil combined treatment intervention group was compared with Donepezil alone, and warm acupuncture improved the MMSE score [MD = 2.03, 95% CI (0.08, 3.98), Z = 2.04, p = 0.04] and effective rate [RR = 1.37, 95% CI (1.01, 1.86), Z = 2.01, p = 0.04] [45].

Fire acupuncture plus Donepezil versus Donepezil

In 1 study that compared fire acupuncture and Donepezil combined intervention treatment with Donepezil monotherapy, fire acupuncture improved the MMSE score [MD = 5.09, 95% CI (4.12, 6.06), Z = 10.32, p < 0.00001], the ADL score [MD = −2.93, 95% CI (−4.45, −1.41), Z = 3.78, p = 0.0002], and the effective rate [RR = 1.31, 95% CI (1.01, 1.70), Z = 2.05, p = 0.04] [47].

Publication bias assessment

Publication bias could not be assessed due to an insufficient number of studies included by intervention and outcome variables.

Discussion

AD accounts for the largest cause of dementia in sufferers, causing a decline in the quality of life for patients (and caregivers) due to the deterioration of cognitive function, decrease of daily living activity, and various BPSD. In addition, with an aging population the prevalence rate of AD will increase, and it is expected that there will be an enormous social and economic expense in the long-term [1].

Acupuncture is the easiest and most accessible treatment for patients in the clinical setting. Li et al. conducted acupuncture in an AD rat model and reported that hippocampal nerve cell loss decreased, and action performance ability increased [50]. Using functional magnetic resonance imaging Zheng et al. reported that acupuncture activated the sections in the brain that related to cognitive function in patients with AD [9]. Similarly, other studies mentioned the potential of acupuncture in the improvement of AD [8,10–12].

AD is diagnosed using as clinical symptoms, cytopathological examination, and radiological findings, and typically, diagnosis is based on The DSM 5, ICD-10 and NINCDS-ADRDA [17]. Some studies grouped AD with senile dementia however, AD is a cause of senile dementia just as vascular cognitive impairment causes dementia making AD difficult to identify. Diagnostic criteria for AD may also be country dependent [51,52]. Thus, this review selected studies where patients were diagnosed with AD based on the diagnostic criteria used most often internationally (e.g. DSM, NINCDS-ADRDA, and ICD-10) and NIA-AA diagnostic criteria which was developed relatively recently [15].

In this review studies using acupuncture, electroacupuncture, fire acupuncture, and warm acupuncture were included, and pharmacopuncture and thread-embedding were excluded. Scalp acupuncture to stimulate the brain was separately classified from acupuncture stimulating the meridian point. Electroacupuncture is applied in parallel with acupuncture to increase the intensity of needle stimulation and add continuous and periodic stimulation. Since the stimulation of electroacupuncture has a different pattern or strength to activate the brain compared with acupuncture [53], it was separately classified, due to the possibility that it may affect the improvement of symptoms of AD.

Western medicine and herbal medicine were used as control groups in the studies included in this review, most studies used Western medicine, in particular Donepezil which is used to improve cognitive function. Donepezil is an acetylcholinesterase inhibitor, inhibiting the breakdown of the neurotransmitter acetylcholine to increase the level and duration of a signal to improve nerve cell communication and cognitive function [4]. Almitrine-Raubasine is a combination drug used for hypomnesia due to senile brain dysfunction, and in 2008 Liu used it in the control group (not currently licensed in South Korea) [54]. Nimodipine is a calcium channel blocker and a potent cerebral vasodilator, mainly used for the treatment of ischemic neuropathy. In the past, it was used to treat AD, but recently, research on the improvement of cerebral blood flow in vascular dementia has been conducted. Of the literature included in this study, 2 studies used Nimodipine in the control group. Maybe nimodipine would be more appropriate for patients with vascular dementia rather than AD [55,56]. Huperzine A is a plant extract that has been reported to have a significant effect on the improvement of cognitive functions of patients with AD and vascular dementia, and as a cholinesterase inhibitor it improves the level of neurotransmitter available. One study reported that in an animal model, Huperzine A had a stronger effect on the suppression of cholinesterase than Donepezil [57], and a meta-analysis study was reported that the MMSE and ADL scores of patients with AD significantly improved [58]. In this review Huperzine A was used as in the control group and was used less frequently than Donepezil [40]. Thus, it is assumed that its use in the clinical setting is low, and it is necessary that further clinical studies are conducted [58].

There were 6 studies that used herbal medicine in the control group, and 6 different prescriptions were used. Angelicae Gigantis Radix was prescribed 3 times, and Salviae Miltiorrhizae Radix, Poria Sclerotium, and Cnidii Rhizoma were used 2 times. Typically, medicine that controls the blood are used [59]. It was difficult to find the relevance between the prescriptions used in each study. However, Korean medicine treatment has the merit that it considers the patient’s symptoms and conditions so, as long as prescriptions are written according to the Pattern Identification within AD in the future, this will support a higher level of evidence.

This review assessed outcome variables from studies that used the MMSE, ADL, and ADAS-cog scores, NPI, and the effective rate of treatment. Many studies used functional magnetic resonance imaging scans and cytopathological examination as outcome variables [35,42,60]. Although it would not be realistic to presume that these tests could be run as the outcome variable in the typical Korean medicine clinical setting. Analysis of the selected literature showed that the MMSE, the screening inspection of dementia, and the assessment of cognitive function was adopted as an outcome variable in most of the selected studies. In addition, the ADL score to assess daily living function, and the effective rate of treatment were adopted in more than half of the studies. However, the frequency of use of the ADAS-cog, another scale to assess cognitive function (8 studies) and the NPI to assess BPSD (1 study) was low. The ADAS-cog comprehensively assesses cognitive function however, it takes a relatively long time (30 minutes) to perform. The MMSE can be conducted in a relatively short time (10 minutes) [17]. So, the ADAS-cog may have a lower priority compared with the MMSE when it is used in the clinical setting. The NPI was utilized in only 1 study, possibly because herbal medicine treatment is the mainstream treating of the BPSD in the clinical setting [61,62]. As a result of an analysis of the outcome variables used, acupuncture focused on the improvements in cognitive function and daily living activity. The effects of acupuncture on the improvement of the BPSD, it is necessary to conduct further study (e.g. A comparison between Western medicine and oriental medicine).

In a comparison between the acupuncture intervention group and the Western medicine control group, there was a statistically significant difference in the MMSE, ADL scores, and effective rates. In a comparison between the acupuncture and Western medicine combined treatment intervention group, there was a statistically significant improvement in the ADL score compared with the Western medicine control group. In a comparison between the electroacupuncture and Western medicine combined treatment intervention group and the Western medicine control group, there was a significant improvement in ADAS-cog score in the combined treatment intervention group. In a comparison between the electroacupuncture and herbal medicine combined treatment intervention group and the herbal medicine control group, the effective rate was statistically significantly higher in the combined treatment intervention group. In a comparison between the scalp acupuncture and Western medicine combined treatment intervention group and the Western medicine control group, there was a statistically significant improvement in the MMSE score in the combined treatment intervention group. In the other comparisons, there were no statistically significant results. To sum up these results, acupuncture treatment improved cognitive function and ability to perform ADL in patients with AD. In some analysis in this literature review, there was no statistically significant difference, this is probably because there was an insufficient number of patients by the intervention and outcome variable, and because there was strong heterogeneity between the studies utilized in the meta-analysis.

This literature review investigated the effects of acupuncture on the symptoms of AD at a higher level of evidence however, this study had some limitations. Firstly, there was not sufficient assessment of the acupuncture for the BPSD of AD. Secondly, all studies included in this review were conducted in China where the treatment method or result may differ depending on the differences in the medical environment and socio-cultural environment so generalizations cannot be made. Thirdly, most of the selected studies had high or unclear RoB. Fourthly, there was a small number of studies and patients included in the meta-analysis (due to strong heterogeneity between the studies). Fifthly, there were insufficient studies that had follow up consultations to determine the long-term effects of acupuncture. However, taking into consideration that the herbal medicine is used in the treatment of the BPSD in AD, additional studies to verify the effect of acupuncture can be combined with herbal medicine. In addition, it would be beneficial to perform randomized controlled trials or long-term observation studies in Korea designed to deliver a higher level of evidence.

Conclusion

Meta-analysis suggests that acupuncture treatment improved cognitive function and improved daily living for patients with AD. However, there was heterogeneity and a high RoB in the studies reviewed. Further research is required to provide a better level of evidence.

Acknowledgments

This work was supported by a National Research Foundation of Korea grant which was funded by the Korean government (no.: 2016R1C1B2016274).

Conflict of Interest

Conflicts of Interest

The authors have no conflicts of interest to declare.

Fig. 1

PRISMA flow chart.

Fig. 2

Risk of bias summary.

Fig. 3

Risk of bias graph.

Fig. 4

Meta-analyses of acupuncture versus Donepezil.

MMSE, mini-mental state examination; AT, manual acupuncture; ADL, activities of daily living; ADAS-cog, the Alzheimer’s disease assessment scale-cognitive subscale.

Fig. 5

Meta-analyses of acupuncture plus Donepezil versus Donepezil.

MMSE, mini-mental state examination; AT, manual acupuncture; ADL, activities of daily living; ADAS-cog, the Alzheimer’s disease assessment scale-cognitive subscale.

Fig. 6

Meta-analyses of (A) acupuncture versus herbal medicine and (B) Meta-analyses of acupuncture plus herbal medicine versus herbal medicine.

AT, manual acupuncture; HM, herbal medicine.

Fig. 7

Meta-analyses of (A) electroacupuncture versus western medicine and (B) meta-analyses of electroacupuncture plus Donepezil versus Donepezil.

MMSE, mini-mental state examination; AT, manual acupuncture; ADL, activities of daily living; ADAS-cog, the Alzheimer’s disease assessment scale-cognitive subscale.

Fig. 8

Meta-analyses of electroacupuncture plus herbal medicine versus herbal medicine.

MMSE, mini-mental state examination; EA, electroacupuncture; HM, herbal medicine; ADL, activities of daily living.

Fig. 9

Meta-analyses of scalp acupuncture plus Donepezil versus Donepezil.

MMSE, mini-mental state examination; SAT, scalp acupuncture; ADL, activities of daily living.

Table 1

Search Strategy in PubMed.

#1. Alzheimer [Title/Abstract] OR Alzheimer Disease [Title/Abstract] OR Alzheimer’s disease [Title/Abstract] OR Alzheimer type dementia [Title/Abstract]
#2. Senile dementia [Title/Abstract]
#3. Alzheim* [Title/Abstract]
#4. #1 or #2 or #3
#5. acupuncture [Title/Abstract] OR acupuncture therapy [Title/Abstract] OR acupuncture treatment [Title/Abstract]
#6. Acupuncture, ear [Title/Abstract] OR ear acupuncture [Title/Abstract] OR Auricular Acupuncture [Title/Abstract]
#7. Acupoint [Title/Abstract] OR acupuncture point [Title/Abstract]
#8. scalp acupuncture [Title/Abstract] OR scalp needl* [Title/Abstract]
#9. Electroacupuncture [Title/Abstract] OR electric acupuncture [Title/Abstract] OR electro-acupuncture [Title/Abstract]
#10. Fire acupuncture [Title/Abstract] OR fire needl* [Title/Abstract]
#11. Warm acupuncture [Title/Abstract] OR warm needl* [Title/Abstract]
#12. Acupunct* [Title/Abstract]
#13. or/#5–#12
#14. #4 AND #13

Table 2

Summary of Included Studies.

Study	Sample size (n)	Acupoints	Groups		Duration	Outcome assessment
Study	Sample size (n)	Acupoints	Treatment intervention	Control	Duration	Outcome assessment
Ou 1999 [18]	30 (16/14)	EA) BL23, EX-HN1, GV20 AT) CV4, LR3, SP36, ST36	EA	WM (Nimodipine Tab. 20–40 mg, 3×d)	8 wk	ADL, Effective rate
Li 2002 [19]	104 (35/37/18/14)	EA) BL23, EX-HN1, GB20, GV20 AT) BL17, LR3, PC6, SP10, SP36, ST40	EA +HM (Dangguijagyak Powder, Alismatis Rhizoma 10 g, Paeoniae Radix 9 g, Atractylodis Rhizoma Alba 9 g, Poria Sclerotium 9 g, Angelicae Gigantis Radix 6 g, Cnidii Rhizoma 6 g, 2×d)	C1) EA C2) HM (Dangguijagyak Powder, Alismatis Rhizoma 10 g, Paeoniae Radix 9 g, Atractylodis Rhizoma Alba 9 g, Poria Sclerotium 9 g, Angelicae Gigantis Radix 6 g, Cnidii Rhizoma 6 g, 2×d) C3) WM (Nimodipine Tab. 20–40 mg, 3×d)	8 wk	MMSE, ADL, Effective rate
Zhao 2007 [20]	32 (16/16)	GV14, GV20	AT	WM (Nimodipine Tab. 20–40 mg, 3×d)	2 mo	Effective rate, MMSE, ADL
Liu 2008 [21]	80 (40/40)	EX-HN3, LI20	AT	WM (Almitrine & Raubasine Tab., 2×d)	10 wk	MMSE, Effective rate
Zhang 2009 [22]	60 (32/28)	HT7, GB39, GV14, GV20, GV26, PC6, SP36 Eye acupuncture) Kidney area, Heart area, Lower energizer area, Upper energizer area	AT +HM (Rehmanniae Radix Preparat 20 g, Salviae Radix 15 g, Cnidii Rhizoma 10 g, Angelicae gigantis Radix 10 g, Polygalali Radix 10 g, Ziziphi Spinosae Semen 10 g, Glycyrrhizae Radix 10 g decoction, 2×d)	HM (Rehmanniae Radix Preparat 20 g, Salviae Radix 15 g, Cnidii Rhizoma 10 g, Angelicae gigantis Radix 10 g, Polygalali Radix 10 g, Ziziphi Spinosae Semen 10 g, Glycyrrhizae Radix 10 g decoction, 2×d)	180 d	Effective rate
Zhu 2010 [23]	80 (20/20/20/20)	BL17, BL23, GV20, SP10	AT +HM (Ikjigeonnoe granules, 3×d)	C1) HM (Ikjigeonnoe granules, 3×d) C2) AT C3) WM (Donepezil Tab. 5 mg, 1×d)	8 wk	Effective rate, MMSE
Yin 2013 [24]	60 (30/30)	MS6 (GV21-GB6), MS7 (GV20-GB7)	SAT +WM (Donepezil Tab. 5 mg, 1×d)	WM (Donepezil Tab. 5 mg, 1×d)	12 wk	MMSE, ADL
Ke 2014 [25]	64 (32/32)	CV6, EX-HN1, EX-HN3, GB39, GV20, SP10, ST36	AT	WM (Donepezil Tab. 5 mg, 1×d)	4 wk	MMSE, ADL, Effective rate
Gu 2014 [26]	141 (72/69)	BL44, GV20, GB20, GB12, CV17, CV12, CV6, SP10, ST36, HT5, SP36, KI3, SP9, ST25, ST40, LR3	AT	WM (Donepezil Tab. 5 mg, 1×d, after 4 wk increases 10 mg)	16 wk	MMSE, ADL, ADAS-cog
Li 2014a [27]	60 (30/30)	GV20, GV14, BL11, BL13, BL15, BL18, BL20, BL23, CV12, ST25, CV4, ST36, ST39, GB39, KI3, LR3, SP36, LR3, ST40, SP10	AT +WM (Donepezil Tab. 5 mg, 1×d)	WM (Donepezil Tab. 5 mg, 1×d)	8 wk	Effective rate, MMSE, ADL, ADAS-cog
Li 2014b [28]	40 (20/20)	Parietal area, Front parietal area, Forehead area	SAT +WM (Donepezil Tab. 5 mg, 1×d)	WM (Donepezil Tab. 5 mg, 1×d)	8 wk	MMSE, ADL
Lin 2014 [29]	36 (18/18)	EA) PC6, SP6 AT) GV20, EX-HN1	EA	WM (Donepezil Tab. 5 mg, 1×d)	12 wk	MMSE, ADAS-cog, ADL
Yang 2014 [30]	60 (30/30)	GV20, EX-HN1, EX-HN3, GB39, BL20, BL23, KI3, ST36	AT	WM (Donepezil Tab. 5 mg, 1×d)	4 wk	MMSE, ADL, Effective rate
Yan 2014 [31]	40 (20/20)	GV24, GB13, LI4 EX-HN1, HT7, KI3, PC6, EX-HN3, LR3, PC5, CV17, CV23, KI6, ST36, GB34, CV6, CV4, SP9, TE17, SI19, GB20, BL10, GB8, ST25	AT	WM (Donepezil Tab. 5 mg, 1×d)	12 wk	MMSE
Ni 2014 [32]	60 (30/30)	GV20, EX-HN1, EX-HN3, GB39, HT7, HT9, LR2, LR3	AT	WM (Donepezil Tab. 5 mg, 1×d)	4 wk	MMSE, ADL, Effective rate
Wang 2014 [33]	55 (27/28)	Coronal suture, Sagittal suture, Lambdoidal suture, Frontotemporal suture, Front frontotemporal suture, Upper frontotemporal suture, Back frontotemporal suture	SAT +WM (Donepezil Tab. 5–10mg once a day)	WM (Donepezil Tab. 5–10 mg, 1×d)	20 d	MMSE, ADAS-cog, Effective rate
Zhang 2014 [34]	60 (30/30)	GV20, EX-HN1, EX-HN3, GB39, ST36, CV12, ST40	AT	WM (Donepezil Tab. 5 mg, 1×d)	4 wk	MMSE, ADL, Effective rate
Liao 2015 [35]	100 (50/50)	MS1, MS5, MS10, MS11	SAT	HM (Ginkgonis Semen extract)	3 mo	MMSE, Effective rate
Liu 2015 [36]	80 (20/20/20/20)	GV20, GV14	AT +HM (Persicae Semen 12 g, Rhei Radix et Rhizoma 9 g, Hirudo 6 g, Tabanus 6 g, Codonopsis Pilosulae Radix 12 g, Astragali Radix 24 g, Poria Sclerotium 18 g, Angelicae Gigantis Radix 12 g, Glycyrrhizae Radix et Rhizoma 6 g decogtion, 1×d)	C1) HM (Persicae Semen 12 g, Rhei Radix et Rhizoma 9 g, Hirudo 6 g, Tabanus 6 g, Codonopsis Pilosulae Radix 12 g, Astragali Radix 24 g, Poria Sclerotium 18 g, Angelicae Gigantis Radix 12 g, Glycyrrhizae Radix et Rhizoma 6 g decogtion, 1×d) C2) AT C3) WM (Donepezil Tab. 5 mg, 1×d)	12 wk	Effective rate
Wang 2015 [37]	72 (36/36)	EA) GV20, GV14	EA	WM (Donepezil Tab. 5 mg, 1×d, after 4 wk increases 10 mg)	12 wk	Effective rate, MMSE
Bi 2016 [38]	74 (37/37)	EA) ST36, ST40	EA	WM (Donepezil Tab. 5 mg, 1×d, after 4 wk increases 10 mg)	12 wk	MMSE, Effective rate
Jia 2017 [39]	79 (40/39)	CV17, CV12, CV6, ST36, TE5, SP10, LR3, GB39, ST40, BL17, ST44, ST25, CV4	AT	WM (Donepezil Tab. 5 mg, 1×d, after 4 wk increases 10 mg)	12 wk	ADAS-cog, NPI
Peng 2017 [40]	50 (25/25)	EA) GV24, GV20, GV14, GV16, KI1 AT) GV4	EA	WM (Huperzine A cap. 0.2 mg, 1×d)	30 d	MMSE, Effective rate
Li 2018 [41]	86 (43/43)	EA) GV20, GV14, GV24, GV16	EA +HM (Bokbangdansampyeon, Salviae Miltiorrhizae Radix, Notoginseng Radix et Rhizoma, Borneolum, 3×d)	HM (Bokbangdansampyeon, Salviae Miltiorrhizae Radix, Notoginseng Radix et Rhizoma, Borneolum, 3×d)	12 wk	MMSE, ADL, Effective rate
Sun 2018 [42]	110 (55/55)	GV20, KI1	AT +WM (placebo, 2 caps, 2×d)	WM (placebo, 2 caps, 2×d)	6 wk	MMSE
Wang 2018 [43]	60 (30/30)	CV17, CV12, SP10, CV6, ST36, TE5, GV20, EX-HN1	AT +WM (Donepezil Tab. 5 mg, 1×d, increases 10 mg)	WM (Donepezil Tab. 5 mg, 1×d, increases 10 mg)	18 wk	MMSE, ADL, ADAS-cog
Chen 2018 [44]	96 (48/48)	GV20, GV26, PC6, SP6, GB39, ST40, KI3	AT +WM (Donepezil Tab. 5 mg, 1×d)	WM (Donepezil Tab. 5 mg, 1×d)	3 mo	Effective rate, ADL, MMSE
He 2018 [45]	60 (30/30)	WAT) GV20, GV14, GV9, GV4 AT) BL23, GB39, KI3	WAT +WM (Donepezil Tab. 5 mg, 1×d)	WM (Donepezil Tab. 5 mg, 1×d)	12 wk	MMSE, Effective rate
Feng 2019 [46]	33 (17/16)	EA) GV20, GV24, EX-HN5 AT) EX-HN3, GV16, KI4	EA	WM (Donepezil Tab. 5 mg, 1×d)	12 wk	MMSE
Zhang 2019 [47]	92 (46/46)	FAT) BL23, BL20, GV20, BL15, ST36, EX-HN1	FAT +WM (Donepezil Tab. 5 mg, 1×d, after 4 wk increases 10 mg)	WM (Donepezil Tab. 5 mg, 1×d, after 4 wk increases 10 mg)	3 mo	MMSE, ADL, Effective rate
Wang 2020 [48]	61 (31/30)	EA) GB15, GB8 AT) GV20, EX-HN3, GB20, LI4, LI11, ST36, LR3	EA +WM (Donepezil Tab. 5 mg, 1×d)	WM (Donepezil Tab. 5 mg, 1×d)	8 wk	Effective rate, MMSE, ADAS-cog
Xia 2020 [49]	60 (30/30)	EA) GV20, GV16	EA +WM (Donepezil Tab. 5 mg, 1×d, after 4 wk increases 10 mg)	WM (Donepezil Tab. 5 mg, 1×d, after 4 wk increases 10 mg)	8 wk	ADAS-cog

E, experimental group; C, control group; EA, electroacupuncture; WM, Western medicine; ADL, Activities of Daily Living; HM, Herbal medicine; MMSE, Mini-Mental State Examination; AT, manual acupuncture; SAT, scalp acupuncture; ADAS-cog, The Alzheimer’s Disease Assessment Scale-Cognitive Subscale; NPI, Dementia NeuroPsychiatric Inventory; WAT, warm acupuncture; FAT, fire acupuncture.

Table 3

Acupoints Used for Each Intervention in Included Studies.

Intervention	Acupoints (frequency used)
Acupuncture	GV20 (15), ST36 (10), GB39, LR3 (9), EX-HN3 (8), EX-HN1, SP10 (7), KI3, ST40 (6), CV6, CV12, SP36 (5), BL23, CV4, CV17, GV14, PC6, ST25 (4), BL17, GB20, HT7 (3), BL20, GV26, LI4, SP9, TE5 (2), BL10, BL11, BL13, BL15, BL18, BL44, CV23, GB8, GB12, GB13, GB34, GV4, GV16, GV24, HT5, HT9, KI1, KI4, KI6, LI11, LI20, LR2, PC5, SI19, SP6, ST39, ST44, TE17 (1)
Electroacupuncture	GV20 (7), GV24, GV16, GV14 (3), EX-HN1, BL23 (2), EX-HN5, GB8, GB15, GB20, KI1, PC6, SP6, ST36, ST40 (1)
Scalp acupuncture	MS1, MS5, MS6, MS7, MS10, MS11, Parietal area, Front parietal area, Forehead area, Coronal suture, Sagittal suture, Lambdoidal suture, Frontotemporal suture, Front frontotemporal suture, Upper frontotemporal suture, Back frontotemporal suture (1)
Warm acupuncture	GV4, GV9, GV14, GV20 (1)
Fire acupuncture	BL15, BL20, BL23, EX-HN1, GV20, ST36 (1)
Eye acupuncture	Kidney area, Heart area, Lower energizer area, Upper energizer area (1)

References

1. Korean Neuropsychiatric Association. Textbook of neuropsychiatry. 3rd ed. Seoul (Korea): I am ez company. 2019:579–589. [in Korean].

2. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 5th ed. Seoul (Korea): Hakjisa. 2017:645–669. [in Korean].

3. Central Dementia Center [Internet]. Dementia disease status. Seoul (Korea): Central Dementia Center, 2020. [updated 2020 Feb 11]. Available from: https://www.nid.or.kr/info/ub_2019.aspx?no=61906.

4. Kim SY. Past and Future of Drug Treatments for Alzheimer’s Disease. J Korean Neuropsychiatr Assoc. 2018;57:30–42. [in Korean].

5. Jeong HG, Han CS. Diagnosis and Treatment of Dementia in Primary Care. J Korean Med Assoc. 2013;56:1104–1112. [in Korean].

6. Koo JS, Seo BI, Park JH, Roh SS. Analysis of papers on Oriental herbal medicines(prescriptions and herbs) for dementia. Korea J Herbalogy. 2010;25:131–137. [in Korean].

7. Lim HS, Kim YJ, Kim YJ, Kim BY, Jeong SJ. Screening of 56 Herbal formulas covered by the National Health Insurance Service on Dementia-related Factors. J Korean Med. 2018;39:1–16. [in Korean].

8. Kim EJ, Choi KH, Jeong HG, Kwon OH, Park JH, Kim SG. Recent RCT Research on the Effects of Acupuncture on Dementia-Based on a PubMed Search of Literature Published from 2000 to 2018. J Int Korean Med. 2018;39:338–349. [in Korean].

9. Zheng W, Su Z, Liu X, Zhang H, Han Y, Song H, et al. Modulation of Functional Activity and Connectivity by Acupuncture in Patients with Alzheimer Disease as Measured by Resting-State fMRI. PLoS ONE. 2018;13:e0196933.

10. Huang Q, Luo D, Chen L, Liang FX, Chen R. Effectiveness of acupuncture for Alzheimer’s disease: An updated systematic review and meta-analysis. Curr Med Sci. 2019;39:500–511.

11. Zhou S, Dong L, He Y, Xiao H. Acupuncture plus Herbal Medicine for Alzheimer’s disease: A systematic review and meta-analysis. Am J Chin med. 2017;45:1327–1344.

12. Zou J, Guo P, Xie K, Dong X, Zhao F. Meta-Analysis of the Effectiveness of Acupuncture Treatment Combined with Traditional Chinese Medicine Treatment of Alzheimer Disease. Acta Chin Med. 2016;31:138–143. [in Chinese].

13. McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan EM. Clinical diagnosis of Alzheimer’s disease: Report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer’s Disease. Neurology. 1984;34:939–943.

14. Dubois B, Feldman HH, Jacova C, DeKosky ST, Barberger-Gateau P, Cummings J, et al. Research criteria for the diagnosis of Alzheimer’s disease: revising the NINCDS-ADRDA criteria. Lancet Neurol. 2007;6:734–746.

15. Lee DY, Sohn BK. New diagnostic criteria for Alzheimer’s disease: NIA-AA diagnostic guidelines. J Korean Geriatr Psych. 2012;16:7–12. [in Korean].

16. World Health Organization. ICD-10 (mental and behavioral disorder). Seoul (Korea): Iljogak. 1998:62–68. [in Korean].

17. Korean Association for Geriatric Psychiatry. Korean assessment scales for dementia patients. Seoul (Korea): Hakjisa. 2012:43–153, 338–345. [in Korean].

18. Ou YQ, Li ZR, Mu YY, Zhao D, Long HW, Wu Q. Comparative Study on Clinical Therapeutic Effect of Acupuncture for Alzheimer′s Disease. Chin Acupunct Moxibustion. 1999;19:399–401. [in Chinese].

19. Li ZR, Mu YY, Ou YQ. Clinic Control Research of Alzheimer’s Disease by the Combination of Acupuncture and Danggui Shaoyao San(DGSYS) of TCM. Chin J Clin Rehabil. 2002;6:2848–2849. [in Chinese].

20. Zhao LG, Ma L, Li YJ, Cheng WP, Wu Q, Zheng ZY, et al. The therapeutic effect observation on acupuncture Baihui and Dazhui for Alzheimer’s disease. J Clin Acupunct Moxibustion. 2007;23:42–43. [in Chinese].

21. Liu ZF, Niu WM, Yang XH, Niu XM. Clinical Study of the Influence of “Xiusanzhen” on Cognitive Competence in Patients with Alzheimer’s Disease. Shaanxi J Tradit Chin Med. 2008;29:711–712. [in Chinese].

22. Zhang S. [Dissertation]. Clinical Observation on Treatment of Senile Dementia with Acupuncture and Medicine. Liaoning. (China): Liaoning University, 2009. [in Chinese].

23. Zhu H, Dong KL, Wu Y, Zhang T, Li RM, Hu SH, et al. Effect of invigorating kidney and activating blood circulation on cognitive function improvement in Alzheimer’s patients. Chin J Gerontol. 2010;30:1493–1495. [in Chinese].

24. Yin HK, Shen XQ, Fu JM, Ren Y, Li L, Shi M. Observation of Curative Effect of Scalp Acupuncture Combined with Aricept Tablet on Alzheimer’s Disease. Chin J Tradit Med Sci Technol. 2013;20:185–187. [in Chinese].

25. Ke YM. [Dissertation]. Clinical Research on Acupuncture Treatment of Qi and Blood Deficiency Type Senile Dementia. Harbin. (China): Heilongjiang University, 2014. [in Chinese].

26. Gu W, Jin XX, Zhang YJ, Li ZJ, Kong Y. Clinical Observation of Alzheimer’s Disease Treated with Acupuncture. Zhongguo Zhen Jiu. 2014;34:1156–1159. [in Chinese].

27. Li QC. [Dissertation]. Clinical Research on Acupuncture Pathway of Qi and Four Sea to Cure Alzheimer’s Disease. Yunnan (China): Yunnan University, 2014. [in Chinese].

28. Li HL, Sun XH, Li M. Clinical Observation of the Effect of Scalp Acupuncture on Patients with Alzheimer’s Disease. J Clin Acupunct Moxibustion. 2014;10:21–22. [in Chinese].

29. Lin CR, Zhang JX, Guo JK, Wang LC, Wang J, Wang XJ, et al. 18 patients cases of Tiaoshen Yizhi acupuncture in the treatment of with mild Alzheimer’s disease. Chin J Gerontol. 2014;34:208–209. [in Chinese].

30. Yang XP. [Dissertation]. Acupuncture Treatment of Spleen Kidney Both Deficiency Type of Senile Dementia Clinical Studies. Harbin (China): Heilongjiang University, 2014. [in Chinese].

31. Yan XZ, Li ZY, Hua QH, Xu L, Jiang Y, Zhang XY. The effect of Tousanshen Acupuncture in the Treatment of Alzheimer’s Disease on Plasma Tau Protein. J Bengbu Med Coll. 2014;39:302–303. [in Chinese].

32. Ni GZ. [Dissertation]. The Clinical Observation on Alzheimer Disease of Heart-Liver Fire Type Treated By Acupuncture. Harbin (China): Heilongjiang University, 2014. [in Chinese].

33. Wang Y, Qin WG, Yu CD. Clinical Observation on Effect of Cranial Suture Acupuncture Combined with Donepezil Hydrochloride Tablets for Alzheimer’s Disease. World J Acupunct Moxibustion. 2014;24:19–24. [in Chinese].

34. Zhang R. [Dissertation]. The Clinical Observation on Alzheimer Disease of Turbid Phlegm Type Treated by Acupuncture. Harbin (China): Heilongjiang University, 2014. [in Chinese].

35. Liao HW, Ji JN, Jiang HY, Wu CF. Effect of Scalp Acupuncture plus Real-time Cognitive Training on Cerebral Blood Flow in Alzheimer Disease Patients. J External Ther Tradit Chin Med. 2015;24:32–34. [in Chinese].

36. Liu J. Effect of Chinese Medicine Combined with Acupuncture on Peripheral Blood TNF-α and IL-6 Expression of Patients with Alzheimer’s Disease. Med Innov China. 2015;30:93–95. [in Chinese].

37. Wang KF, Zhang LJ, Chen XY. Clinical Observation on 36 Cases of Alzheimer’s Disease Treated by Electro-acupuncture Dazhui(GV14) and Baihui(GV20). Chin J Tradit Chin Med. 2015;30:784–786. [in Chinese].

38. Bi DY, Liu Q, Chen YX, Zou YF, Ma MZ, Li D, et al. Therapeutic Observation on Electroacupuncture at Zusanli (ST 36) and Fenglong (ST 40) for Senile Dementia. J Acupunct Tuina Sci. 2016;14:386–390.

39. Jia YJ, Zhang XZ, Yu JC, Han JX, Yu T, Shi JW, et al. Acupuncture for Patients with Mild to Moderate Alzheimer’s Disease-A Randomized Controlled Trial. BMC Complement Altern Med. 2017;17:556–563.

40. Peng J, Chen X, Wang AP, Luo L, Zhou B, Zhang HY. Efficacy Evaluation on Electroacupuncture for Alzheimer’s Disease. J Acupunct Tuina Sci. 2017;15:296–299.

41. Li JP, Zeng YH, Lu W, Jiang ZD, Yang L. Clinical observation on electroacupuncture combined with compound Danshen tablets in the treatment of Alzheimer’s disease. China Modern Doc. 2018;56:64–67. [in Chinese].

42. Sun HN, Zhu MD, Zhang W. Effects of Serum Acetyl Choline and Amyloid-Beta Protein by Using Acupuncture Baihui(GV20) and Yongquan(KI1) Acupoint to Treat Patients with Alzheimer Disease. World Chin Med. 2018;13:2855–2857. [in Chinese].

43. Wang Y, Zhao L, Kan BH. Effect of Sanjiao Acupuncture on Alzheimer’s Syndrome Patients Life Quality and Immune Function. Liaoning J Tradit Chin Med. 2018;45:2403–2406. [in Chinese].

44. Chen DR, Zheng YX, Chen MZ. Therapeutic Effects of Acupuncture on Senile Dementia and Its Influence on Cytokine and Blood Lipid Metabolism. World Chin Med. 2018;13:719–721. [in Chinese].

45. He XH. [Dissertation]. Clinical Research on Warming Moxibustion in the Improvement of Kidney Efficiency and Marrow Insufficiency type Alzheimer’s Disease Patients with Cognitive Functions. Shandong (China): Shandong University, 2018. [in Chinese].

46. Feng Q, Bin LL, Zhai YB, Xu M, Liu ZS, Peng WN. Long-term efficacy and safety of electroacupuncture on improving MMSE in patients with Alzheimer’s disease. Zhongguo Zhen Jiu. 2019;39:3–8. [in Chinese].

47. Zhang KB, Yang YH, Ding J. Clinical Observation on Fire Needle Combined with Oral Donepezil in the Treatment of Alzheimer’s Disease. Guangming J Chin Med. 2019;34:291–293. [in Chinese].

48. Wang YH, Wang Y, Zhou X, Cui HS. Clinical Observation of Needing Qin’s eight Head Acupoints Combined with Western Medicine in the Treatment of Alzheimer’s Disease. Shanghai J Tradit Chin Med. 2020;54:69–73. [in Chinese].

49. Xia KP, Pang J, Li SL, Zhang M, Li HL, Wang YJ. Effect of Electroacupuncture at Governor Vessel on Learning-memory Ability and Serum Level of APP, Aβ1-42 in Patients with Alzheimer’s Disease. Zhongguo Zhen Jiu. 2020;40:375–378. [in Chinese].

50. Li GM, Zhang XZ, Cheng HY, Shang XM, Xie H, Zhang X, et al. Acupuncture Improves Cognitive Deficits and Increases Neuron Density of the Hippocampus in Middle-aged SAMP8 Mice. Acupunct Med. 2012;30:339–345.

51. Tian JZ, Shi J, Wei MQ. Diagnostic accuracy of the operational criteria for the diagnosis of Alzheimer’s disease (Beijing version). Alzheimers Dement. 2014;10:724.

52. Lee SJ, Han JH, Hwang JW, Paik JW, Han CS, Park MH. Screening for Normal Cognition, Mild Cognitive Impairment, and Dementia with the Korean Dementia Screening Questionnaire. Psychiatry Investig. 2018;15:384–389.

53. Jacqueline F, Adrian W, Mike C. Medical acupuncture. 2nd ed. Seoul (Korea): Hanmiuihak, 2019. 168–170. [in Korean].

54. Druginfo. Duxil Tab^® [Internet]. Seoul (Korea): Druginfo, [updated 2020 May 11]. Available from: https://www.druginfo.co.kr/detail/product.aspx?pid=390.

55. Grobe-Einsler R, Traber J. Clinical results with Nimodipine in Alzheimer disease. Clin Neuropharmacol. 1992;15:416–417.

56. Zhang XL, Zheng SL, Dong FR, Wang ZM. Nimodipine improves regional cerebral blood flow and suppresses inflammatory factors in the hippocampus of rats with vascular dementia. J Int Med Res. 2012;40:1036–1045.

57. Wang R, Yan H, Tang XC. Progress in Studies of Huperzine A, a Natural Cholinesterase Inhibitor from Chinese Herbal Medicine. Acta Pharmacol Sin. 2006;27:1–26.

58. Xing SH, Zhu CX, Zhang R, An L. Huperzine A in the Treatment of Alzheimer’s Disease and Vascular Dementia: A Meta-Analysis. Evid Based Complement Alternat Med. 2014;2014:363985.

59. Ju YS. Ungok Herbology. 2nd ed. Jeonju (Korea): Woosuk Press. 2013:708–712, 937–941, 963–965, 1303–1309. [in Korean].

60. Shan Y, Wang JJ, Wang ZQ, Zhao ZL, Zhang M, Xu JY, et al. Neuronal Specificity of Acupuncture in Alzheimer’s Disease and Mild Cognitive Impairment Patients: A Functional MRI Study. Evid Based Complement Alternat Med. 2018;2018:7619197.

61. Hyde AJ, May BH, Dong L, Feng M, Liu S, Guo X, et al. Herbal medicine for management of the behavioural and psychological symptoms of dementia (BPSD): A systematic review and meta-analysis. J Psychopharmacol. 2017;31:169–183.

62. Mizukami K, Asada T, Kinoshita T, Tanaka K, Sonohara K, Nakai R, et al. A randomized cross-over study of a traditional Japanese medicine (kampo), yokukansan, in the treatment of the behavioural and psychological symptoms of dementia. Int J Neuropsychopharmacol. 2009;12:191–199.