Clinical Neurology and Neurosurgery 213 (2022) 107134

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Clinical Neurology and Neurosurgery

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Efficacy and safety of donepezil for mild cognitive impairment: A

systematic review and meta-analysis
Xuemei Zhang a, b, Siheng Lian a, b, Yingshi Zhang a, b, *, Qingchun Zhao a, b, **
a
Department of Pharmacy, General Hospital of Northern Theater Command, No.83, Wenhua Road, Shenhe District, Shenyang, 110840, China.
b
Department of Clinical Pharmacy, Shenyang Pharmaceutical University, Shenyang, 110016, China.

A R T I C L E I N F O A B S T R A C T

Keywords: Objective: This study intends to systematically evaluate the efficacy and safety of donepezil for improving
Mild cognitive impairment cognitive function in patients with mild cognitive impairment (MCI), and to provide evidence-based foundation
Donepezil for donepezil in MCI treatment.
Meta-analysis
Methods: We searched in PubMed, Embase, Cochrane Library, Clinical trials.gov, Web of Science, CQVIP, and
Efficacy
Safety
CNKI databases, and then we summarized the interventional and observational studies on the use of donepezil for
improving the cognitive function of MCI patients. The literature was collected according to the inclusion criteria
for data extraction. We evaluated the quality of the selected literature and used Stata 15.0 for meta-analysis.
Results: A total of 12 randomized controlled trials (RCTs) and 5 non-randomized concurrent controlled trials
(CCTs) were included, and a total of 2847 patients were included. In terms of efficacy, meta-analysis showed that
donepezil could significantly improve the MMSE (SMD: 0.85, 95%CI: 0.40–1.31) and MoCA (SMD: 1.88, 95%CI:
0.32–3.45) scores of MCI patients. Donepezil could not significantly reduce ADAS-cog score, nor could it
significantly delay disease progression. The quality of the evidence was low overall. In terms of safety, donepezil
could significantly increase the risk of adverse reactions such as nausea, vomiting, diarrhea in patients with MCI.
Conclusion: Donepezil can improve the cognitive function of MCI patients to a certain extent. However, there is
no trend of significantly delaying the progression of the disease, and it is easy to lead to the occurrence of adverse
reactions.

1. Introduction
Mild cognitive impairment (MCI) is a transitional state between
normal decline of memory due to aging and dementia [1]. It is a com­
bination of clinical manifestations, cognitive state, cognitive function
and other standard defined syndromes [2]. Based on the result of a
summary analysis, the average annual conversion rate of MCI to de­
mentia is 4.2% [3]. While, in other short-term clinical observations, the
annual conversion rate can be as high as 10–15% [4]. The risk of
developing dementia in MCI patients is significantly higher than that of
healthy individuals, and as the disease progresses, it may eventually lead
to the occurrence of adverse outcomes such as death [5,6]. Therefore,
active interventions may play an important role in improving cognitive
functions and delaying the progression of this disease. As of now, there
are no FDA approved drugs for the treatment of MCI [7]. Donepezil is
currently the most commonly used drug for the treatment of dementia
and cognitive symptoms of MCI in clinical trials at home and abroad, but
its effectiveness in the treatment of MCI requires further elucidation
[8–11]. Some studies have shown that current evidences do not support
the use of cholinesterase inhibitors for treating MCI [12]. In addition,
Schuff et al. [13] find that donepezil is associated with slowed pro­
gression of whole brain atrophy, which implies a possible
disease-modifying effect. To explore further, in this study, meta-analysis
was used to evaluate the efficacy and safety of donepezil in the treat­
ment of MCI.
2. Materials and methods
This study was written according to the Preferred Reporting Items for
Systematic Reviews and Meta-Analyses guidelines [14], and was

* Corresponding author at: Department of Clinical Pharmacy, Shenyang Pharmaceutical University, Shenyang, 110016, China.
** Corresponding author at: Department of Pharmacy, General Hospital of Northern Theater Command, No.83, Wenhua Road, Shenhe District, Shenyang, 110840,
China.
E-mail addresses: zxm9511@163.com (X. Zhang), lsiheng@163.com (S. Lian), syzys1990@sina.com (Y. Zhang), zhaoqingchun1967@163.com (Q. Zhao).

https://doi.org/10.1016/j.clineuro.2022.107134
Received 10 December 2020; Received in revised form 11 January 2022; Accepted 12 January 2022
Available online 19 January 2022
0303-8467/© 2022 Elsevier B.V. All rights reserved.

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X. Zhang et al.
registered with the International Prospective Register of Systematic
Reviews in advance.(CRD42020198782).
2.1. Search strategy
We searched Pubmed, Embase, Cochrane Library, Clinical trials.gov,
Web of Science, CQVip and CNKI, and manual search of references was
also joint. The search terms were: "donepezil[Mesh]", "donepezil",
"Aricept", "E2020", "MCI", "mild cognitive impairment", "cognitive
dysfunction[Mesh]". The period of literature search was from the date of
database construction to June 2020.
2.2. Inclusion criteria
(1) Study design: Both intervention and observation studies were
included.
(2) Research subjects: Any ones who met the MCI diagnostic criteria
and were not restricted by age, gender, country, race and
etiology.
(3) Intervention: The treatment group was given any dose of done­
pezil or combined with basic treatment, and the control group
was given placebo or conventional treatment.
(4) Outcome: The main outcome indicators included Mini-mental
state examination scale (MMSE), Alzheimer’s disease assess­
ment scale-cognitive subscale (ADAS-cog) and Montreal Cogni­
tive assessment scale (MoCA). The secondary outcome indicators
included the number of patients who progressed to dementia
during the trial and the occurrence of various adverse reactions.
2.3. Exclusion criteria
(1) The original literature was a review, a meta-analysis or a case
report.
(2) Repeated reports or literature with incomplete information and
unavailable data.
(3) Studies with insufficient diagnostic evidence of MCI.
2.4. Data extraction
After reading the full text of the included literature by two re­
searchers, relevant materials were extracted and cross-checked. The
extracted information included the first author, year of publication,
region, type of study, sample size, age, follow-up time, intervention and
outcome indicators.
2.5. Literature quality evaluation and evidence quality evaluation
For randomized controlled trials, Cochrane risk-of-bias criteria was
used to evaluate the quality of the literature. For non-randomized con­
current controlled trials, the methodological index for non-randomized
studies (MINORS) scale was used to assess the quality of the study [15].
Finally, GRADEpro software was used to assess the quality of the
evidence.
2.6. Statistical method
We used Stata 15.0 for statistical analysis of the data. The specific
content included: (1) Calculation of the combined effect size. Contin­
uous variables were expressed by standardized mean difference (SMD)
and 95% CI, and binary variables were expressed by risk ratio (RR) and
95% CI. When P < 0.05, the statistical difference was considered sig­
nificant. (2) Heterogeneity test. The Q test and I2 value were used to
measure the heterogeneity among studies. When P < 0.1 and I2≥ 50%,
the heterogeneity between studies was considered to be great, and the
source of heterogeneity was further analyzed. If there was no clinical
heterogeneity, a random effects model would be used to perform a meta-
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Clinical Neurology and Neurosurgery 213 (2022) 107134
analysis. When P ≥ 0.1 and I2< 50%, the inter-study heterogeneity was
considered to be small, and the fixed effects model would be used for
meta-analysis. (3) Begg’s and Egger’s tests were used for publication
bias test with a significance level of 0.05. (4) We used subgroup analysis
and meta-regression to find the source of heterogeneity. When P < 0.05,
the difference was considered statistically significant.
3. Results
3.1. Literature search results
According to the search strategy, 1904 articles were initially
retrieved, and 17 articles that met the criteria were finally included
[8–11,16–28]. A total of 12 randomized controlled trials and 5
non-randomized concurrent controlled trials, including 2847 patients,
were analyzed. The literature screening process is shown in Fig. 1. The
basic characteristics of the included studies are shown in Table 1. The
literature quality evaluation results are shown in Fig. S1 and Table S1.
The quality of the literature is generally high.
3.2. Efficacy outcomes
To investigate whether donepezil has the effectiveness of improving
the cognitive function of MCI patients, we used MMSE, ADAS-cog, and
MoCA scores to evaluate the changes in patients’ cognitive function. We
also analyzed the number of patients who progressed to dementia during
the trial to see if donepezil could delay the progression of MCI.
3.2.1. MMSE
As shown in Fig. 2 and Table 2, 12 articles [9,11,16,19,21–28]
applied MMSE score to evaluate the efficacy of donepezil. The hetero­
geneity test indicated that there was a high degree of heterogeneity
among the studies (I2=95.1%, P = 0.000), and the division into RCT and
CCT subgroups did not reduce the heterogeneity within the groups, so a
random effects model was used for meta-analysis. The results showed
that compared with the control group, donepezil significantly improved
the patient’s MMSE score (SMD: 0.85, 95%CI: 0.40–1.31). Whether in
the RCT subgroup or the CCT subgroup, we could observe this differ­
ence. At the same time, Begg’s test (P = 0.732) and Egger’s test
(P = 0.195) suggested that there was no publication bias. The GRADE
score showed that the quality of the evidence was very low.
To further explore the source of its heterogeneity, we conducted a
meta-regression and other subgroup analysis. As shown in Table 2, when
subgroups were distinguished by duration of intervention, the subgroup
with a course of more than 2 years showed increased MMSE score, but
no longer had a significant difference between the experimental group
and the control group (SMD: 2.06, 95%CI: − 1.78 to 5.90). When dis­
tinguishing subgroups by region, donepezil significantly increased the
MMSE score (SMD: 1.10, 95%CI: 0.38–1.81) only when the subjects
were from Asia. When the subgroups were divided by dose, only when
the dose of donepezil was 5 mg/d, donepezil significantly increased the
MMSE score (SMD: 1.48, 95% CI: 0.51–2.45), and the remaining doses
showed no significant difference. When distinguishing subgroups by
type of disease, we observed that the heterogeneity within the subgroup
of amnestic MCI (aMCI) was significantly reduced (I2=0%, P = 0.679),
and the heterogeneity within the remaining subgroup, whose classifi­
cation of MCI was unclear, was still high. This indicated that type of the
disease might be the source of heterogeneity. At the same time, the aMCI
subgroup showed a tendency to improve MMSE score, but did not show
a significant difference, indicating that the type of MCI might also be the
source of the difference in the efficacy of donepezil.
At the same time, we conducted a meta-regression for these five
factors: region, study design, duration of intervention, dose and type of
MCI. The results showed that none of the above factors could affect the
final results, and the heterogeneity of the results might be related to
other unknown factors.
X. Zhang et al. Clinical Neurology and Neurosurgery 213 (2022) 107134

Fig. 1. flow diagram of included studies.

Table 1
Summarized designs of the included studies and the baseline characteristics.
First author Year of Country Age n Intervention (dose, mg/day) Study duration
publication design
Test Control Test group Control group
group group

Salloway S 2004 America 55–90 132 137 Donepezil(5 mg/d, 10 mg/ placebo DBRCT 24 weeks
d after 42d)
Petersen RC 2005 America, 55–90 253 259 Donepezil(5 mg/d, 10 mg/ placebo DBRCT 3 years
Canada d after 6 weeks)
Doody RS 2009 America 45–90 409 412 Donepezil(5 mg/d, 10 mg/ placebo DBRCT 48 weeks
d from 6th week)
Yu LL 2013 China No 32 28 Donepezil(10 mg/d) Conventional treatment RCT 12
limitation months
Dubois B 2015 France > 50 113 103 Donepezil(5 mg/d, 10 mg/ placebo DBRCT 52 weeks
d after 6 weeks)
Montero- 2018 Canada > 65 31 29 Donepezil(5 mg/d, 10 mg/ placebo DBRCT 6 months
Odasso M d after 4 weeks)
Reynolds CF 2011 America ≥ 65 30 27 Antidepressant treatment + Antidepressant DBRCT 24
Donepezil(5 mg/d) treatment + placebo months
Gu XY 2011 China 55–80 33 34 Donepezil(5 mg/d) Conventional treatment RCT 12 weeks
Ke TX 2015 China No 75 75 Donepezil(5 mg/d) Conventional treatment RCT 3 years
limitation
Devanand DP 2018 America 55–95 30 31 Antidepressant treatment + Antidepressant DBRCT 48 weeks
Donepezil(5–10 mg/d) treatment + placebo
Yark〉n Özenli 2007 Turkey No 26 25 Donepezil(5 mg/d, 10 mg/ Conventional treatment RCT 24 weeks
limitation d after 30d)
Wang ZQ 2007 China No 50 50 Donepezil(5 mg/d, 10 mg/ Conventional treatment RCT 1 year
limitation d after 1 month)
Peng DT 2007 China ≥ 55 42 56 Donepezil(5 mg/d) No Intervention CCT 2 years
Ran SL 2010 China ≥ 55 33 27 Donepezil(5 mg/d) No Intervention CCT 12
months
Wang LN 2004 China 55–85 21 12 Donepezil(2.5 mg/d) Conventional treatment CCT 3 months
Zhang B 2008 China No 45 44 Donepezil(5 mg/d) Conventional treatment CCT 6 months
limitation
Zhang LF 2016 China No 72 71 Donepezil(5 mg/d) Conventional treatment CCT 24 weeks
limitation

DBRCT: double-blind randomized controlled trial.

CCT: concurrent controlled trials.

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X. Zhang et al. Clinical Neurology and Neurosurgery 213 (2022) 107134

Fig. 2. Forest plot of MMSE.

3.2.2. ADAS-cog
We also inspected ADAS-cog score. As shown in Fig. 3 and Table 2,
five articles [8–10,16,24] applied the ADAS-cog score to evaluate the
efficacy of donepezil in the treatment of MCI. The heterogeneity test
indicated that there was a high degree of heterogeneity among the
studies (I2=98.8%, P = 0.000). The division into RCT and CCT sub­
groups did not reduce the heterogeneity within the subgroups, and then
the random effects model was used for meta-analysis. The results
showed that compared with the control group, the treatment with
donepezil had a tendency to reduce the ADAS-cog score of MCI patients,
but the difference was not statistically significant (SMD: − 0.53, 95%CI:
− 1.54 to 0.48). There was no significant difference whether in the RCT
subgroup or in the CCT subgroup. At the same time, Begg’s test
(P = 0.806) and Egger’s test (P = 0.581) suggested that there was no
publication bias. The GRADE score showed that the quality of the evi­
dence was very low.
patients (SMD: 1.88, 95%CI: 0.32–3.45). This difference could be
observed in both of the RCT subgroup and the CCT subgroup. But the
Egger’s test (P = 0.037) suggested that there was a certain publication
bias. The GRADE score showed that the quality of the evidence was low.
3.2.4. Progression of MCI to dementia
We also conducted a statistical analysis of the number of MCI pa­
tients whose disease progressed to dementia during the trial. As shown
in Fig. S2, a total of 4 studies [9,20,24,25] mentioned this indicator. The
heterogeneity test suggested that there was no heterogeneity among the
studies (I2=15.0%, P = 0.317), and a fixed effects model was used for
meta-analysis. The results showed that treatment of donepezil had a
tendency to delay the progression of MCI compared with the control
group, but the difference was not statistically significant (RR: 0.78, 95%
CI: 0.60–1.02).

3.2.3. MoCA 3.3. Safety outcomes

We also inspected the MoCA score. As shown in Table 2, 4 articles
[17,19,21,25] applied MoCA score to evaluate the efficacy of donepezil.
The heterogeneity test suggested that the heterogeneity among the
studies was high (I2=96.0%, P = 0.000), and the division into RCT and
CCT subgroups did not reduce the heterogeneity. Random effects model
was used for meta-analysis. The results showed that compared with the
control group, donepezil significantly improved the MoCA score of MCI
We conducted statistics on common adverse reactions that occurred
during the course of the trial, and 5 articles [8,9,16,18,19] participated
in the statistics. As shown in Fig. 4 and Table 3, the heterogeneity test
suggested that there was a high degree of heterogeneity among the
studies (I2=96.5%, P = 0.000), and the random effects model was used
for meta-analysis. The results showed that donepezil was more likely to
cause adverse reactions than placebo (RR: 1.64, 95%CI: 1.13–2.38). At

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Table 2
Subgroup analyses and meta-regression in Efficacy outcomes.
Outcome Subgroups Donepezil Control SMD (95%CI) Heterogeneity (P, Quality of Meta-regression Publication bias
(n) (n) I2) evidence (P)
Begg’s Egger’s
(P) (P)

MMSE Total(n ¼ 12) 1049 1056 0.85(0.40, P = 0.000, Very low 0.732 0.195
1.31)a I2= 95.1%
Study design
RCT(n = 7) 836 846 0.89(0.23, P = 0.000, Low 0.893 0.652 0.353
1.55)a I2= 96.8%
CCT(n = 5) 213 210 0.81(0.27, P = 0.000, Very low 1.000 0.965
1.35)a I2= 84.8%
Region
North America(n = 3) 652 662 0.22(− 0.13, P = 0.001, Very low 0.195 0.602 0.604
0.57) I2= 85.6%
Asia(n = 9) 397 394 1.10(0.38, P = 0.000, Very low 0.404 0.567
1.81)a I2= 95.0%
Dose
2.5 mg/d(n = 1) 21 12 0.40(− 0.32, – Very low 0.127 – –
1.11)
5 mg/d(n = 6) 300 307 1.48(0.51, P = 0.000, Very low 0.260 0.230
2.45)a I2= 96.3%
10 mg/d(n = 5) 728 737 0.26(− 0.02, P = 0.001, Very low 0.462 0.571
0.54) I2= 78.9%
Duration of
intervention
≤ 2 years(n = 10) 721 722 0.63(0.33, P = 0.000, Very low 0.173 0.531 0.700
0.94)a I2= 82.4%
＞2 years(n = 2) 328 334 2.06(− 1.78, P = 0.000, Very low 0.317 –
5.90) I2= 99.4%
Type of MCIb
aMCI(n = 2) 45 45 0.28(− 0.15, P = 0.679, Very low 0.493 0.317 –
0.70) I2= 0.0%
No limitation(n = 11) 1004 1011 0.90(0.41, P = 0.000, Very low 0.938 0.193
1.38)a I2= 95.5%
ADAS- Total(n ¼ 5) 834 856 -0.53(− 1.54, P = 0.000, Very low 0.806 0.581
cog 0.48) I2= 98.8%
Study design
RCT(n = 4) 792 800 -0.63(− 1.81, P = 0.000, Very low – 0.734 0.721
0.55) I2= 99.0%
CCT(n = 1) 42 56 -0.14(− 0.54, – Very low – –
0.26)
MoCA Total(n ¼ 4) 118 114 1.88(0.32, P = 0.000, Low 0.308 0.037c
3.45)a I2= 96.0%
Study design
RCT(n = 3) 85 87 0.62(0.31, P = 0.446, Moderate – 1.000 0.883
0.92)a I2= 0.0%
CCT(n = 1) 33 27 6.15(4.92, – Low – –
7.38)a
a
This symbol means that there is a significant difference between the experimental group and the control group.
b
When distinguishing subgroups by type of MCI, the patients included in Peng DT’s study can be divided into aMCI and non-aMCI patients. Therefore, the study is
divided into two studies to be included in the statistics in this subgroup analysis.
c
This symbol means that publication bias may exist in the included literature.

the same time, Begg’s test (P = 0.086) and Egger’s test (P = 0.243)
suggested that there was no publication bias. The GRADE score showed
that the quality of the evidence was moderate.
In addition, we had detailed observations on the occurrence of
adverse reactions. As shown in Table 3, the results showed that for the
adverse events such as nausea/vomiting, diarrhea/loose stools, muscu­
loskeletal and connective tissue diseases, insomnia/fatigue, headache/
dizziness, and abnormal dreams, the donepezil treatment group had a
higher risk, and the difference was statistically significant. The GRADE
score showed that the quality of the evidence was high.
4. Discussion
In this study, we found that the use of donepezil significantly
increased the MMSE and MoCA scores of MCI patients, but it could not
significantly reduce the ADAS-cog score, nor could it significantly delay
the disease progression. The above results are similar to the results of
Briks [29]. In their study, they pointed out that the use of donepezil had
certain benefits in the improvement of cognitive functions in patients
with MCI, but there was not enough evidence to support its use in the
treatment of MCI. This is also consistent with the findings of Kishi [30]
et al. In their study, anti-dementia drugs prevented the increase of
ventricular volume in patients with MCI with relatively large effect size,
which may account for the efficacy of donepezil in MCI patients. How­
ever, the absence of significant protective effect in the hippocampus may
indicate that the efficacy of donepezil is limited. In addition, our
research showed that the use of donepezil could significantly increase
the risk of multiple adverse reactions. The above conclusions are
consistent with many studies [29,31]. Therefore, we seem to be able to
draw the conclusion that donepezil has a certain effect on improving the
cognitive functions of patients with MCI, but it also increases the risks of
adverse reactions. Therefore, donepezil may not be recommended as an
essential therapeutic agent for MCI. However, although it has been re­
ported in the literature that cholinesterase inhibitors cannot improve
cognition in MCI patients [12], given the fact that donepezil does have
some cognition-improving effects based on the literature and our results
[29,32], we believe that future high-quality RCTs are necessary.
There are limited clinical trials at home and abroad to explore the

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X. Zhang et al.
Fig. 3. Forest plot of ADAS-cog, CCT: concurrent controlled trials.
efficacy of donepezil in MCI patients. Therefore, RCT and CCT were both
included in the search process to increase the sample size. However,
subgroup analysis based on factors such as dose, duration of interven­
tion, type of MCI, region, and study design did not eliminate the high
degree of heterogeneity among studies, suggesting that the heteroge­
neity was more likely to originate from the studies themselves.
MCI is the most successful entity of the predementia state. According
to the Diagnostic and Statistical Manual of Mental Disorders (DSM-5),
MCI and “Minor Neurocognitive Disorder” (miNCD) are two currently
most frequently employed diagnostic entities covering predementia
states [33]. However, the clinical use of miNCD instead of MCI requires
more scientific evidence [34]. So we only selected MCI patients as our
research subjects. However, we have also observed that when the MCI
type in clinical trials was clearly specified, as in the subgroup of
amnestic MCI in this study, there was no heterogeneity among studies
within this subgroup, indicating that the types of MCI might also be a
source of heterogeneity. However, due to the small number of docu­
ments included in this subgroup, the evidence was insufficient. In
addition, the above factors also did not show significant differences in
meta-regression analysis, suggesting that the heterogeneity might come
from other unknown factors. The above conclusions provide a reference
for the design of subsequent similar clinical trials, that is, when
exploring whether donepezil has a curative effect on MCI, the control of
MCI type may result in more credible results.
MCI can be further classified as amnesic MCI, non-amnesic MCI, and
mixed MCI [35]. In our study, donepezil failed to show a significant
improvement in the cognitive functions of patients with amnesic MCI.
However, a secondary analysis by Edmonds et al. [36] showed that
donepezil might be an effective treatment for amnesic MCI, and its
therapeutic effect might have been covered by the crowd, which was
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Clinical Neurology and Neurosurgery 213 (2022) 107134
included in the MCI cohort of clinically-recognized individuals, that is,
"false positive MCI diagnosis". It is indicated that the short latency
afferent inhibition (SAI), a transcranial magnetic stimulation protocol,
may give direct information about the function of some cholinergic
pathways in the human motor cortex. In the research of Nardone [37],
Mean SAI, a putative marker of central cholinergic activity, differed
among MCI subtypes and SAI was increased after administration of a
single dose of donepezil in a subgroup of amnestic MCI patients. This
may mean that the type of MCI may affect the efficacy of donepezil, but
further verification is still needed. The patients in the clinical trials
included in this study were diagnosed with MCI based on the existing
diagnostic criteria, without clinical imaging features and cerebrospinal
fluid biomarkers [38], and the absence of these subjective factors might
cause heterogeneity of the subjects, thereby reducing the credibility of
the test results.
In addition, in the course of this study, we found some interesting
results. When distinguishing subgroups by regions, donepezil signifi­
cantly increased the MMSE score only when the subjects were from Asia.
This difference was no longer significant when the subjects were from
North America. Due to limited research available, we were unable to
obtain more trial data on other races. Besides, some studies [39] showed
that the efficacy of donepezil for MCI patients was related to the
apolipoprotein E (ApoE) genotype. The carrier of the ApoEε4 genotype
responded more positively to donepezil, but there are also studies which
drew opposite conclusions in AD patients [40]. Similarly, the butyr­
ylcholinesterase (BChE) gene, a susceptibility gene for AD, has also been
shown to be related to the efficacy of donepezil. The use of donepezil in
BChE K-positive MCI subjects can achieve greater benefits [41]. There
are also studies showing that BCHE K and APOEε4 carriers should not be
prescribed off-label donepezil therapy for MCI management [42]. It has
X. Zhang et al. Clinical Neurology and Neurosurgery 213 (2022) 107134

Fig. 4. Forest plot of ADRs.

Table 3
Meta-analysis in Safety outcomes.
Outcome Tevent Tsample Cevent Csample RR (95%CI) Heterogeneity (P, Quality of Publication bias
(n) (n) (n) (n) I2) evidence
Begg’s Egger’s
(P) (P)

Total ADRs(n = 5)a 769 920 509 915 1.64(1.13, 2.38)b P = 0.000, Moderate 0.086 0.243
I2= 96.5%
Nausea/Vomiting(n = 5) 116 837 39 843 3.01(2.12, 4.27)b P = 0.725, High 1.000 0.574
I2= 0.0%
b
Diarrhea/loose stools(n = 5) 172 837 53 843 3.29(2.46, 4.40) P = 0.184, High 0.221 0.280
I2= 35.6%
b
Musculoskeletal and connective 130 837 20 843 6.43(4.08, 10.14) P = 0.972, High 0.806 0.762
tissue disorders (n = 5) I2= 0%
Insomnia/fatigue(n = 5) 85 837 35 843 2.45(1.68, 3.58)b P = 0.324, High 0.462 0.491
I2= 14.1%
Headache/dizziness(n = 3) 42 452 20 447 2.08(1.25, 3.46)b P = 0.741, High 1.000 0.837
I2= 0.0%
b
Abnormal dreams(n = 5) 83 837 22 843 3.81(2.41, 6.02) P = 0.410, High 0.221 0.246
I2= 0.0%

Tevent: Number of events in test group; Tsample: Sample size of test group; Cevent:Number of events in control group; Csample: Sample size of control group.
a
This analysis did not include clinical studies where the number of adverse events in the experimental group> the sample size of the experimental group.
b
This symbol means that there is a significant difference between the experimental group and the control group.

been demonstrated that the proportion of APOE4 carriers is higher in 5. Conclusion

North America than in Asia [43]. The variation in genetic poly­
morphisms may have contributed to the differences in drug efficacy. Donepezil can improve the cognitive function of MCI patients to a
Unfortunately, there are currently limited clinical trials that explore the certain extent. However, there is no trend of significantly delaying the
effects of ApoE and BChE genotypes on the efficacy of donepezil. In the progression of the disease, and it is easy to lead to the occurrence of
meta-analysis of the same kind we retrieved, there is no statistics about adverse reactions.
this question. However, with the development of precision medicine, it
is obviously necessary to further explore the efficacy of donepezil in MCI Declarations of interest
patients harboring those susceptibility genes.
None.

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November 07, 2023. For personal use only. No other uses without permission. Copyright ©2023. Elsevier Inc. All rights reserved.
X. Zhang et al.
Funding
This research did not receive any specific grant from funding
agencies in the public, commercial, or not-for-profit sectors.
Authorship
ZXM, ZYS, and ZQC designed the research; ZXM, LSH and ZYS con­
ducted research; ZXM and LSH analysed data; ZXM, ZYS, and ZQC wrote
the first draft of the paper; ZQC had primary responsibility for final
content. All authors are involved in writing the article.
Appendix A. Supporting information
Supplementary data associated with this article can be found in the
online version at doi:10.1016/j.clineuro.2022.107134.
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