The value of cholinesterase inhibitors for improving neuropsychiatric and functional assessment scores in patients with Alzheimer disease: a systematic review and meta-analysis of on placebo-controlled RCTs

Abstract

Introduction:

At present, increasing reports from different aspects indicated that cholinesterase inhibitors (ChEIs) may be effective on improving neuropsychiatric and functional assessment scores in patients with Alzheimer disease (AD). However, no studies comprehensively and detailedly evaluated the effect of ChEIs on AD. The present analysis was designed to comprehensively evaluate the efficacy and safety of ChEIs for AD.

Methods:

Two independent researchers systematically reviewed 1096 searching records in PubMed, Embase, Cochrane Library, and Web of Science from inception to 10 May 2023, and finally identified 12 randomized, double-blind, placebo-controlled trials with 6908 participants according to predetermined inclusion and exclusion criteria. The effects were assessed with standardized mean difference (SMD) or odds ratio (OR). The primary outcomes were the mean change and least squares (LS) mean change from baseline to endpoint of neuropsychiatric and functional assessment scores. The secondary outcome was adverse events of ChEIs when compared to placebo for patients with AD. All statistical analyses were performed using the standard statistical procedures provided in Review Manager 5.2 and and Stata 12.0.

Results:

Pooled analysis indicated that ChEIs significantly improved the assessment scores of the AD Assessment Scale (ADAS) (SMD −1.57; 95% CI: −2.64 to −0.51), Clinician’s Interview-Based Impression of Change-Plus caregiver input (CIBIC-Plus) (SMD −0.28; 95% CI: −0.41 to −0.15), the Neuropsychiatric Inventory (NPI) (both SMD −1.67; 95% CI: −2.88 to −0.47 for 10-tiem total score and SMD −1.83; 95% CI: −3.25 to −0.42 for 12-tiem total score), and the AD Cooperative Study–Activities of Daily Living (ADCS-ADL) total score (SMD 2.44; 95% CI: 1.29–3.59), evaluated with mean change from baseline to endpoint. In addition, when evaluated with the LS mean change from baseline to endpoint, ChEIs significantly improved Mini-Mental State Examination (MMSE) total score, the Clinician Interview-Based Impression of Severity, CIBIC-Plus, ADCS-ADL total score, NPI, ADAS. Regarding to adverse events (AEs) of patients with AD, it indicated that compared to placebo, ChEIs did not increase the frequency of severe and serious AEs (fatal or nonfatal) as well as the incidence of death.

Conclusions:

Our analysis indicated that ChEIs treatment generally improved neuropsychiatric and functional assessment scores in patients with AD though opposite result was observed in Wechsler Memory Scale. ChEIs had an acceptable safety profile in patients with AD without increasing of any crucial adverse or outcomes.

Introduction

Highlights

• Cholinesterase inhibitors (ChEIs) treatment improved neuropsychiatric and functional assessment scores in patients with Alzheimer’s disease (AD).

• ChEIs had an acceptable safety profile in patients with AD.

• However, it was indicated that ChEIs may lead to deterioration in Wechsler Memory Scale.

• The intolerance of ChEIs always focused on gastrointestinal (GI) system.

Alzheimer’s disease (AD), which was first described by Alois Alzheimer at a meeting of South-West Germany Psychiatrists in 1906¹, has been well known at present and has become the most common type of dementia. Increases in life expectancy in the last century have resulted in a large number of people living to old ages and will result in a quadrupling of AD cases by the middle of the century². It was estimated that, the number of people in the United States with AD will increase dramatically in the next 40 years, and by 2050, the total number of people with AD is projected to be 13.2 million (almost threefold of the number in 2010), with the majority of patients aged more than 85 years^3,4.

AD is a neurodegenerative old age disease that is complex, multifactorial, unalterable, and progressive in nature⁵. Thus, the detailed etiology and pathogenesis of AD is still not clear at present. According to recent researches, AD was not only a spontaneous disease, but also was associated with traumatic brain injury which could increase the risk of dementia or AD^6–9. D’Souza GM (2024) found that among those with AD, traumatic brain injury was associated with an earlier age of AD onset but, counterintuitively, less cortical thinning in frontotemporal regions relative to non-AD controls⁷.

Patients who progress to the severe stage of AD have markedly diminished cognitive and functional abilities, reduced social interaction, and their capacity to perform instrumental activities of daily living (ADLs) is significantly compromised¹⁰. While basic ADLs can be carried out to varying degrees, impairments in such ADLs as bathing and toileting are common. Given the burden that dementia in general, which affects about 18 million people worldwide¹¹, and AD in particular, represents for patients, their families, and the health care system, there is great interest in the development of therapeutic approaches that will lessen the human and financial costs associated with these disease states. Neuronal loss and subsequent disruption of brain neurochemistry are thought to underlie the symptoms of AD, and treatment approaches to date have largely focused on enhancing cholinergic activity in the brain¹².

AD always impairs cognitive function and memory as well as activities of daily, resulting in deterioration of neuropsychiatric and functional assessment scores. Convergent evidence from neuroimaging and biochemistry studies showed that the development of psychosis is related to a cholinergic deficiency in AD¹³. Therefore, cholinesterase inhibitors (ChEIs) could be effective treatments for neuropsychiatric and functional assessment scores in AD, with better tolerability compared with antipsychotics and benzodiazepines. Several case series, open label trials, and post-hoc analyses reported a marked improvement of assessment scores in AD after ChEIs treatment. Previous meta-analysis with randomized clinical trials (RCTs) demonstrated the effects of ChEIs on neuropsychiatric symptoms in AD¹⁴. However, there has been no consistent consensus and clear conclusion being conducted at present. The present meta-analysis comprehensively reviewed, compared, and evaluated the effect of ChEIs on various neuropsychiatric and functional assessment scores in patients with AD.

Methods

Search strategy and study selection

Systematic search was performed using a search strategy developed by a medical information specialist that involved controlled vocabulary and keywords relating to (1) ‘Alzheimer’s disease’ OR ‘dementia’; (2) ‘cholinesterase inhibitors’ OR ‘ChEIs’ OR ‘Donepezil’ OR ‘Galantamine’; (3) ‘effect’ OR ‘effectiveness’ OR ‘outcome’ OR ‘efficacy’ OR ‘safety’ OR ‘adverse event’. Search formula was (1) AND (2) AND (3). The search strategy was limited to English language articles. Two independent researchers systematically reviewed 1096 searching records in PubMed, Embase, Cochrane Library, and Web of Science from inception to 10 May 2023, according to the strategy above. All references were imported into Endnote, version X9 (Clarivate) for removal of duplicates and left 644 records. Manual screening of the references in the included articles was also conducted for a more comprehensive search. Two assessors independently screened the titles and abstracts of each study and 588 studies were excluded preliminarily and 56 studies were chosen to get full texts for further evaluation. When a relevant study was identified, its full text was obtained for further evaluation. The full text of related references was also obtained for review. Any disagreement was handled by discussion with a third reviewer. After reading the full texts, 44 studies were excluded further and finally we identified 12 randomized, double-blind, placebo-controlled trials with 6908 participants according to predetermined inclusion and exclusion criteria. The detailed search process and summary of studies are shown in the study flow diagram (Fig. 1).

Figure 1.

Flow diagram of literature search and selection of included studies for meta-analysis.

Measurements for efficacy assessment

The efficacy of ChEIs for patients with AD was assessed by the mean change or least squares (LS) mean change from baseline to endpoint of Mini-Mental State Examination (MMSE), Functional Assessment Staging (FAST), Severe Impairment Battery (SIB), Clinician’s Interview-Based Impression of Change-Plus caregiver input (CIBIC-Plus), the Alzheimer Disease Cooperative Study–Activities of Daily Living–severe version (ADCS-ADL-sev), the Neuropsychiatric Inventory (NPI), the Alzheimer’s Disease Assessment Scale (ADAS), the Clinician Interview-Based Impression of Severity (CIBIS), Wechsler Memory Scale (WMS). Increasing in scores of MMSE, ADCS-ADL, WMS, and QoL-AD and decreasing in scores of other measurement scales indicated ameliorative effectiveness.

Criteria for considering studies

Studies that met the following criteria (PICOS) was included: a. patients diagnosed with AD; b. ChEIs used as intervention; c. placebo used as controlling; d. the mean change and least squares (LS) mean change from baseline to endpoint of the assessment scores including ADAS, CIBIC-Plus, NPI, ADCS-ADL total score, MMSE total score, CIBIS score and WMS; or adverse events were reported; e. Phase II / III placebo-controlled randomized studies.

Studies were excluded if they met the following criteria: a. experimental trial on animals or a nonhuman study; b. nonplacebo-controlled RCTs; c. study population included patients with other diseases that would affect outcomes; d. study reported in the form of an abstract, letter, editorial, expert opinion, review, or case report; or e. lack of sufficient data or fail to meet the inclusion criteria.

Quality assessment and data extraction

Two reviewers assessed the quality of each study using the validated five-point Jadad scale¹⁵. In addition, the risk of bias for each studies and the risk of bias across all studies were evaluated and shown with figures generated by RevMan 5.2 software¹⁶. Funnel plot generated by Stata 12.0 (Stata Corp.) was used to evaluate and show publication bias.

Baseline characteristics and outcomes from the included studies were extracted using a standardized extraction form. Key study characteristics including countries and centers, sample size, severity of dementia, age, intervention, age, duration, neurologic, and cognitive test scores and end points were extracted. Data were extracted by one reviewer and then examined for accuracy and completeness by a second reviewer. Any disagreement was handled by discussion with a third reviewer.

Data synthesis, statistical methods, and definitions

The data of comparable outcomes were combined-analyzed, using the standard statistical procedures provided in RevMan 5.2¹⁶ and Stata 12.0 (Stata Corp.). In this meta-analysis, the standardized mean difference (SMD) or odds ratio (OR) was used to assess the treatment effect, with a 95% CI. The heterogeneity between studies was evaluated by the χ²-based Q statistical test¹⁷, with P value and I² statistic, ranging from 0 to 100%, to quantify the effect of heterogeneity. P≤0.10 was deemed to represent significant heterogeneity¹⁸, and pooled estimates were estimated using a random-effect model (the DerSimonian and Laird method¹⁹). On the contrary, if statistical study heterogeneity was not observed (P>0.10), a fixed effects model (the Mantel–Haenszel method²⁰) was used. The effects of outcome measures were considered to be statistically significant if pooled MDs with 95% CI did not overlap with 0, or pooled HRs and ORs with 95% CI did not overlap with 1. Funnel plot were prepared to detect publication bias. If the shape of the funnel plot reveals no obvious evidence of asymmetry, we considered that there was no obvious publication bias. All statistical analyses were performed using standard statistical procedures provided in RevMan 5.2¹⁶ and Stata 12.0 (Stata Corp.).

This work has been reported in line with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA)²¹ and Assessing the methodological quality of systematic reviews (AMSTAR) Guidelines²². The present research was registered in researchregistry https://researchregistry.knack.com/research-registry#registryofsystematicreviewsmeta-analyses/registryofsystematicreviewsmeta-analysesdetails/653a477cb7a42000295fb6f2/.

Results

Included studies, study characteristics, and quality assessment

Eventually, 12 randomized, double-blind, placebo-controlled trials^23–34 with 6908 participants were identified included in this systematic review and meta-analysis. Among the 12 RCTs we included, 8 studies were designed as multicenter RCTs the sample size ranged from 208 patients to 1195 patients. The mean age of patients included in the present analysis was more than 70 years. The duration of intervention ranged from 3 months to 6 months and 9 studies sustained there intervention with 6 months. The other characteristics of each study are shown in Table 1.

Table 1.

The characteristics of included RCTs for meta-analysis.

Author (year)	Country and site	Sample size (n)	Severity of dementia	Intervention	Age (year)	Duration	Neurologic and cognitive test scores	End points or outcomes
Black SE (2007)23	Multinational,98 sites	343	MMSE 1-12; FAST ≥ 6; MHIS ≤ 6	Donepezil, 10 mg daily	78.0±8.10	24 weeks	SIB, CIBIC-Plus, MMSE, FAST, ADCS-ADL-sev, NPI, CBQ, RUSP	Mean and LS change from baseline to endpoint, AEs
Brodaty H (2005)24	Five countries at 93 sites	971	MMSE 10-24; ADAS-cog/11 ≥ 18	Galantamine 16 or 24 mg/day	76.5±7.81	6 months	ADAS-cog/11, CIBIC-Plus, ADCS-ADL, NPI	Mean change from baseline, AEs
Gault LM (2016)25	NR	438	MMSE 10-24; CSDD ≤ 10; MHIS ≤ 4	ABT-126 25 / 50 / 75 mg, donepezil 10 mg, QD	74.2±7.89	24 weeks	ADAS, MMSE, WMS, ADCS-ADL total score, NPI-12-item total score	mean change from placebo, AEs
Gault LM (2015)26	Six countries at 27 sites	274	MMSE 10-24; CSDD ≤ 10; MHIS ≤ 4	ABT-126 (5 or 25 mg once daily), donepezil 10 mg once daily	73.9±7.92	24 weeks	11-item ADAS-Cog total score, ADAS-Cog 13-item total score, MMSE, CIBIS and CIBIC-Plus, NPI-12-item total score, ADCS-ADL total score	LS and mean change from placebo, AEs
Gold M (2010)27	One hundred thirty-four centers in 19 countries	693	MMSE 10-23	2 mg RSG XR, 8 mg RSG XR or 10 mg donepezil	72.5±8.56 71.7±7.91 72.6±8.63 72.9±7.97	24 weeks	ADAS-Cog total scores, CIBIC+ scores,	Change from baseline, AEs
Haig GM (2014)28	Two countries in 21 sites	242	MMSE 10-24; CSDD ≤ 10; MHIS ≤ 4	ABT-288 1 mg or 3 mg, donepezil 10 mg, once daily	70.2±8.32	12 weeks	13-item ADAS-Cog Total Score, 11-item ADAS-Cog Total Score, MMSE Total Score, NPI (12-item) Total Score, NPI (10-item) Total Score, ADCS-ADL Total Score	Mean change from baseline, AEs
Homma A (2008)29	Japan	325	MMSE 1-12; MHIS ≤ 4; FAST ≥ 6	Donepezil 5 or 10 mg/day	79.7±7.5 78.0±8.9 76.9±7.9	24 weeks	SIB, CIBIC-plus, ADCS-ADL-sev, BEHAVE-AD	LS mean change from baseline; AEs
Nakamura Y (2011)30	NR	855	MMSE 10-20	4.5 mg loading dose, 9 mg loading dose, 13.5 mg loading dose and 18 mg loading dose	74.5±7.4 74.3±7.5 75.1±6.9 74.6±7.2	24 weeks	ADAS J-cog scores, CIBIC-plus-J scores	LS mean changes from baseline; AEs
Rockwood K (2001)31	Six countries at 43 sites	386	MMSE 11-24	galantamine received 8 mg/day for 1 week, increasing to 16 mg/day for the 2nd week and to 24 mg/day for the 3rd	74.6±0.68 75.2±0.45	3months	ADAS-cog/11, ADAS-cog/13, NPI, DAD	AEs
Tariot PN (2001)32	US in 27 sites	208	MMSE 5-26	Donepezil, average daily dose of 9.5 mg/day	85.9 (65–102) 85.4 (64–98)	24 weeks	Mean NPI-NH 12-item total scores	Response, AEs
Tariot PN (2000)33	United States, multicenter	978	MMSE 10-22	Galantamine 8 mg/day, 16 mg/day, 24 mg/day	77.1±0.5 76.0±0.6 76.3±0.5 77.7±0.4	5 months	ADAS-cog, CIBIC-plus, NPI,	mean change from baseline, AEs
Winblad B (2007)34	NR	1195	MMSE 10-20	Three active treatment target dose groups	73.6±7.9 74.2±7.7 72.8±8.2 73.9±7.3	24 weeks	ADAS-cog, ADCS-CGIC, ADCS-ADL, NPI, MMSE	Mean changes at Week 24 to placebo, AEs

ADAS, the Alzheimer’s Disease Assessment Scale; ADCS-ADL-sev, the Alzheimer Disease Cooperative Study–Activities of Daily Living–severe version; CBQ, the Caregiver Burden Questionnaire; CIBIC-Plus, Clinician’s Interview-Based Impression of Change-Plus caregiver input; CIBIS, the Clinician Interview-Based Impression of Severity; CSDD, Cornell Scale for Depression in Dementia; FAST, Functional Assessment Staging; MHIS, Modified Hachinski Ischemic Scale; MMSE, Mini-Mental State Examination; NPI, the Neuropsychiatric Inventory; NR, not report; RUSP, the Resource Utilization for Severe Alzheimer Disease Patients; SIB, Severe Impairment Battery; WMS, Wechsler Memory Scale.

All of our included studies experienced good quality. The risk of bias for each study was presented as percentages across all included studies, and the risk-of-bias item for each included study was displayed in Supplementary Figure S1 and S2, Supplemental Digital Content 1, http://links.lww.com/JS9/C323. According to our assessment, the risk-of-bias graphs indicated generally low risk of selection, performance and detection bias. Unclear risk of bias was mainly observed in attrition bias and other bias. No high risk of bias was observed in our assessment.

Effect of ChEIs on mean change from baseline of neuropsychiatric and functional assessment scores

Pooled analysis indicated that, when compared to placebo, ChEIs significantly improved ADAS (SMD −1.57; 95% CI: −2.64 to −0.51), CIBIC-Plus (SMD −0.28; 95% CI: −0.41 to −0.15), NPI (both SMD −1.67; 95% CI: −2.88 to −0.47 for 10-tiem total score and SMD −1.83; 95% CI: −3.25 to −0.42 for 12-tiem total score), and ADCS-ADL total score (SMD 2.44; 95% CI: 1.29–3.59), evaluated with mean change from baseline to endpoint. However, no significant difference between ChEIs and placebo was found in MMSE total score (SMD 0.06; 95% CI: −0.07 to 0.18) and CIBIS score (SMD 0.07; 95% CI: −0.11 to 0.24). Inversely, deterioration in WMS was observed in ChEIs arm when compared with placebo, with a pooled SMD of −1.86 (95% CI: −3.54 to −0.17). The pooled analysis above is performed using fixed-effect models because no significant heterogeneity was observed (P _{heterogeneity} >0.10) (Fig. 2).

Figure 2.

Forest plot showing the effect of cholinesterase inhibitors on mean change from baseline to endpoint of neuropsychiatric and functional assessment scores. SMD, standardized mean difference; MMSE, Mini-Mental State Examination; ADAS, the Alzheimer’s Disease Assessment Scale; CIBIS, the Clinician Interview-Based Impression of Severity; CIBIC-Plus, Clinician’s Interview-Based Impression of Change-Plus caregiver input; NPI, the Neuropsychiatric Inventory; ADCS-ADL, the Alzheimer Disease Cooperative Study–Activities of Daily Living. The pooled analysis above is performed using fixed-effect model.

Effect of ChEIs on LS mean change from baseline of neuropsychiatric and functional assessment scores

In addition, we also evaluated and compared the effect of ChEIs on neuropsychiatric and functional assessment scores by LS mean changes from baseline to endpoint. When compared to placebo, ChEIs significantly improved MMSE total score (SMD 0.67; 95% CI: 0.04–1.29), CIBIS-plus (SMD −2.69; 95% CI: −4.06 to −1.32), CIBIC-Plus (SMD −1.23; 95% CI: −1.57 to −0.89), ADCS-ADL total score (SMD 2.50; 95% CI: 1.72–3.28), NPI (both SMD −1.20; 95% CI: −1.91 to −0.49 for total score and SMD −0.80; 95% CI: −1.49 to −0.12 for 10-tiem total score), ADAS (SMD −2.42; 95% CI: −3.13 to −1.71 for total scores, SMD −3.83; 95% CI: −4.92 to −2.74 for cog/11 and SMD −2.15; 95% CI: −3.22 to −1.07 for cog/13) and CIBIC-plus-J MENFIS score (SMD −0.17; 95% CI: −0.29 to −0.05) (Fig. 3).

Figure 3.

Forest plot showing the effect of cholinesterase inhibitors on the least squares (LS) mean change from baseline to endpoint of neuropsychiatric and functional assessment scores. SMD, standardized mean difference; MMSE, Mini-Mental State Examination; ADAS, the Alzheimer’s Disease Assessment Scale; CIBIS, the Clinician Interview-Based Impression of Severity; CIBIC-Plus, Clinician’s Interview-Based Impression of Change-Plus caregiver input; NPI, the Neuropsychiatric Inventory; ADCS-ADL, the Alzheimer Disease Cooperative Study–Activities of Daily Living; WMS, Wechsler Memory Scale. The pooled analysis above is performed using random-effect model.

However, no significant difference between ChEIs and placebo was found in ADCS-ADL-sev (SMD 0.57; 95% CI: −0.85 to 1.98), NPI 12-tiem total score (SMD −0.02; 95% CI: −0.74 to 0.70), QoL-AD, Subject total score (SMD −0.89; 95% CI: −2.02 to 0.24), and CIBIC-plus-J BEHAVE-AD score (SMD 0.14; 95% CI: −0.13 to 0.41). Inversely, it was indicated that ChEIs lead to a deterioration in QoL-AD-Caregiver total score (SMD −0.57; 95% CI: −0.98 to −0.16), CIBIC-plus-J DAD score (SMD 2.81; 95% CI: 0.89–4.73), and WMS (SMD −1.55; 95% CI: −2.97 to −0.14) (Fig. 3).

Safety

We evaluated the safety of ChEIs for AD by comparing the adverse events (AEs) between ChEIs and placebo. Our results indicated that compared to placebo, ChEIs did not increase the incidence of both severe (OR 1.25; 95% CI: 0.86–1.81) and serious AEs (OR 1.00; 95% CI: 0.83–1.20). The incidence of death in ChEIs arms and placebo arms was also similar (OR 0.91; 95% CI: 0.52–1.58). However, ChEIs lead to more frequency of AEs from any cause (OR 1.38; 95% CI: 1.25–1.53). More patients with AD discontinued treatment due to AEs in ChEIs arms than placebo arms with a pooled OR of 1.47 (95% CI: 1.21–1.80). In addition, patients receiving ChEIs experienced higher incidence of any related AEs with a pooled OR of 1.60 (95% CI: 1.35–1.89) (Table 2).

Table 2.

Overview of comparison between ChEIs and placebo for Alzheimer disease regarding to adverse events.

		Pooled results from FEM
Adverse events	Sample size	OR	95% CI
AEs from any cause	7819	1.38	1.25–1.53
Discontinued due to AEs	6202	1.47	1.21–1.80
Severe AEs	3720	1.25	0.86–1.81
Serious AEs (fatal or nonfatal)	7064	1.00	0.83–1.20
Any related AEs	3369	1.60	1.35–1.89
Deaths	4502	0.91	0.52–1.58

AEs, adverse events; FEM, fixed-effect model; OR, odds ratio.

The material of this article is original research. All data in this manuscript is available and transparent for readers.

Tolerability

We further evaluated the tolerability of ChEIs for AD comprehensively by comparing AEs according to different systems. As result, ChEIs showed similar incidence of AEs in body as a whole, respiratory system, urinary system, cardiovascular events, musculoskeletal, skin, and other AEs (MedDRA preferred term). However, the intolerance of ChEIs always focused on gastrointestinal GI system, with significant difference of AEs between ChEIs and placebo. It indicated that ChEIs indicated the incidence of GI system disorders (OR 1.78; 95% CI: 1.44–2.21), anorexia (OR 2.14; 95% CI: 1.62–2.83), nausea (OR 2.86; 95% CI: 2.32–3.52), diarrhea (OR 1.46; 95% CI: 1.16–1.83), vomiting (OR 2.54; 95% CI: 1.97–3.28), and constipation (OR 2.48; 95% CI: 1.43–4.30). In addition, the difference of several AEs was also observed in agitation / anxiety (OR 1.32; 95% CI: 1.05–1.65), depression (OR 2.03; 95% CI: 1.19–3.48), central and peripheral nerve system disorders (OR 1.60; 95% CI: 1.24–2.07), dizziness (OR 2.32; 95% CI: 1.61–3.34), weight loss (OR 2.71; 95% CI: 1.62–4.53), peripheral edema (OR 1.62; 95% CI: 1.11–2.36), and hyperlipidemia (OR 5.23; 95% CI: 1.60–17.04) (Supplemental Table, Supplemental Digital Content 2, http://links.lww.com/JS9/C324).

Publication bias

Begg’s funnel plot with pseudo 95% confidence limits were conducted for assessing and showing publication bias of included literatures and we could assess the publication bias by seeing whether their shapes were of any obvious asymmetry. According to Figure 4 showing, no clear evidence of publication bias was observed in the literatures (P=0.063).

Figure 4.

Funnel plot with pseudo 95% confidence limits showing publication bias.

Discussion

AD is the primary cause of dementia and is characterized by the death of brain cells due to the accumulation of insoluble amyloid plaques, hyperphosphorylation of tau protein, and the formation of neurofibrillary tangles within the cells. AD is also associated with other pathologies such as neuroinflammation, dysfunction of synaptic connections and circuits, disorders in mitochondrial function and energy production, epigenetic changes, and abnormalities in the vascular system. Despite extensive research conducted over the last hundred years, little is established about what causes AD or how to effectively treat it³⁵. In addition, it was found that AD with traumatic brain injury represented a distinct group from AD, likely with distinct pathologic contributions beyond gray matter loss⁷, which had important implications for the diagnosis and treatment of AD in the presence of traumatic brain injury and indicated that models of AD, aging, and neural loss should account for traumatic brain injury history. Currently, ChEIs as one of available medications focusing on correcting the neurotransmitter disruption was observed effective on AD and could temporarily alleviated the signs of dementia. Several RCTs have explored the efficacy of ChEIs for AD and observed different results in different neuropsychiatric and functional assessment scores. Thus, we reviewed and analyzed the effect of ChEIs for patients with AD via different assessment scores with a total of 12 randomized, double-blind, placebo-controlled trials including 6908 participants. Our results indicated that ChEIs could improve the scores of the majority assessment measurement scales. In addition, ChEIs showed similar safety in serious or sever AEs and equal tolerance in many aspects when compared to placebo.

Our pooled results indicated that ChEIs had significant effectiveness for patients with AD in improving ADAS, CIBIC-Plus, NPI total score, ADCS-ADL total score, MMSE total score, and CIBIS. Though Gault LM (2015)²⁶ indicated no significant improvement of ChEIs in MMSE, CIBIS, CIBIC-Plus, and ADCS-ADL total score, our pooled results negated this results and found that ChEIs had significant effectiveness in the scores above. However, our results demonstrated no obvious improvement in NPI 12-item total score which was consistent with the results of Gault LM (2015)²⁶. Mean NPI 12-item total scores for both groups were improved relative to baseline at all assessments from Week 4, but there were no statistically or clinically significant differences observed in change from baseline between treatment groups, at any assessment. There were also no significant differences observed between the treatment groups when the NPI individual item scores were analyzed as quantitative scores for change from baseline at endpoint³². Significant improvement was observed in MMSE total score in our analysis and differences in mean change from baseline MMSE score favored ChEIs at all time-points and were statistically significant at Weeks 8, 16, and 20³². Before our analysis, only one meta-analysis by d’Angremont et al.¹⁴, which aimed to quantitatively assess the use of ChEIs for treatment of individual neuropsychiatric symptoms in patients with AD, Parkinson disease, and dementia with Lewy bodies and found that ChEIs treatment improved psychotic symptoms in patients with AD and Parkinson disease with small effect sizes. The authors did not explore the tolerance of ChEIs. The results used to evaluate psychotic symptoms were extracted from the assessment scales in our analysis. Thus, this result from d’Angremont et al.¹⁴ supported our results to some extent.

Several limitations in our work should be acknowledged. First, there was heterogeneity in the intervention of our included studies. The drugs and the dose in the trials were different as showing in Table 1. However, limited to the sample size, we failed to perform subgroup analysis according to different drugs and the dose. Second, our included studies evaluated different severity of dementia of AD patients assessing with different criteria including MMSE, ADAS-cog/11, FAST, MHIS and CSDD. Some studies evaluated mild to moderate AD and others evaluated severe AD. Several did not state the severity of AD in their trials. Considering the association between the severity of AD and the assessment scores, this inconsistency may lead to any risk of bias which may influence our results. Third, the duration of intervention in our included studies ranged from 12 weeks to 6 months. The effect of ChEIs or the assessment scores changed over time. The majority of studies evaluated the effect of ChEIs at the endpoint with 24 weeks. However, some studies found that the difference of assessment scores between treatment arms and control arms changed over time and would reach a plateau. Thus, future researches should dynamically observe the effectiveness of ChEIs and found an optimal duration and the long term effect of ChEIs should be cleared in the future.

Conclusions

The results of this meta-analysis suggested that ChEIs treatment had beneficial effect on patients with AD. Pooled results indicated that ChEIs treatment generally improved neuropsychiatric and functional assessment scores in patients with AD though opposite result was observed in Wechsler Memory Scale. ChEIs had an acceptable safety profile in patients with AD without increasing of any crucial adverse or outcomes. ChEIs had good tolerance in many aspects except in gastrointestinal tract.

Ethical approval

Ethical approval is not applicable.

Sources of funding

Natural Science Foundation of Gansu Province [Grant Number: 22JR5RA679. Gansu Provincial Hospital Cultivation Project [Grant Number: ZX-62000001-2022-169]. Gansu Provincial Hospital Science and Technology Innovation Platform Project [Grant Number: ZX-62000001-2021-210].

Author contribution

The authors on this paper all participated in study design. All authors read, critiqued and approved the manuscript revisions as well as the final version of the manuscript. Also, all authors participated in a session to discuss the results and consider strategies for analysis and interpretation of the data before the final data analysis was performed and the manuscript written. All authors have the appropriate permissions and rights to the reported data.

Conflicts of interest disclosure

The authors declare no relevant conflicts of interest.

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Guarantor

Jianping Wang.

Provenance and peer review

Not commissioned, externally peer-reviewed.

Supplementary Material

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