The Efficacy and Safety of Alzheimer’s Disease Therapies: An Updated Umbrella Review

Abstract

Background:

Evidence summaries for efficacy and safety of frequently employed treatments of Alzheimer’s disease (AD) are sparse.

Objective:

We aimed to perform an updated umbrella review to identify an efficacious and safe treatment for AD patients.

Methods:

We conducted a search for meta-analyses and systematic reviews on the Embase, PubMed, The Cochrane Library, and Web of Science to address this knowledge gap. We examined the cognitive functions, behavioral symptoms, global clinical assessment, and Activities of Daily Living as efficacy endpoints, and the incidence of adverse events as safety profiles.

Results:

Sixteen eligible papers including 149 studies were included in the umbrella review. The results showed that AChE inhibitors (donepezil, galantamine, rivastigmine, Huperzine A), Ginkgo biloba, and cerebrolysin appear to be beneficial for cognitive, global performances, and activities of daily living in patients with AD. Furthermore, anti-Aβ agents are unlikely to have an important effect on slowing cognitive or functional impairment in mild to moderate AD.

Conclusion:

Our study demonstrated that AChE inhibitors, Ginkgo biloba, and cerebrolysin are the optimum cognitive and activities of daily living medication for patients with AD.

Keywords

Acetylcholinesterase inhibitors Alzheimer’s disease anti-Aβ agents systematic review umbrella review

INTRODUCTION

Alzheimer’s disease (AD) is a neurodegenerative disease that affects the elderly and is the most common form of dementia. The disease is clinically characterized by cognitive deterioration, loss of functional ability, and behavioral changes [1]. Patients with AD have poor self-reliance, which imposes a heavy burden on their families, caregivers, health care system, and the society at large [2]. Moreover, there are more than 47 million people with AD worldwide, and the number is estimated to triple in the next 30 years [3]. At present, the key challenge in the treatment of AD is to identify the best way to implement the efficacious interventions currently available.

Some evidence supports the hypothesis that AD is pathologically caused by the presence and accumulation of brain amyloid-β (Aβ) [4]. In addition, studies on Aβ-targeting agents have been the main direction of AD therapeutic in recent years [5]. Nevertheless, anti-Aβ immunotherapy has been shown to effectively remove Aβ plaques, many clinical trials have failed to reverse the cognitive impairment of patients with AD [6, 7]. Anti-Aβ agents are known to block Aβ generation and aggregation, the acetylcholinesterase inhibitors (AChEIs) are widely used by inhibiting the activity of acetylcholinesterase (AChE) and delaying the hydrolysis rate of acetylcholine [8]. Additionally, as an N-methyl-D-aspartate (NMDA) receptor antagonist, memantine has an eff-ect on moderate cognitive and functional benefits [9]. Furthermore, other antidementia drugs are supported by comprehensive clinical reports that demonstrate their efficacy and safety in improving cognitive impairment or other major domains [10, 11].

There are many systematic reviews and meta-anal-yses analyzing the treatments of AD. Those studies, however, did not provide a comprehensive appraisal of AD therapies [8, 12]. Therefore, the present study aimed to perform an umbrella review of the systematic reviews and meta-analyses of AD therapies through a comprehensive and updated literature search, and to reach a clear conclusion by integrating all available meta-analyses to identify an efficacious and safe treatment for AD patients that are commercially available.

MATERIALS AND METHODS

Our study was performed in accordance with the standard guidelines of Preferred Reporting Items for Systematic reviews and Meta-analysis (PRISMA) [13].

Search strategy and quality assessment

A systematic search of published peer-reviewed English-language literature was conducted using PubMed, Embase, Web of Science, and The Cochrane Library until September 2021. The database search terms were as follows: (Alzheimer’s disease) and (systematic review or meta-analysis) and clinical trial. We included meta-analyses and systematic reviews that determined the efficacy and safety of treatments in patients with AD. Inclusion criteria were: 1) written in English; 2) published systematic review or meta-analyses; 3) including any evaluation of clinical assessment scales for AD; 4) published in peer-reviewed journals. Studies were excluded if 1) unpublished studies; 2) no necessary sample data; 3) patients were diagnosed with other dementia; 4) study reported insufficient details and other outcomes.

The AMSTAR tool was used to evaluate systematic reviews and meta-analyses [14]. The methodological quality of the studies was determined by the percentage of AMSTAR score. The percentage of AMSTAR score was classified into 0–33%, 34–66%, and 67% –100% indicating low quality, medium quality, and high quality, respectively.

Data extraction

The main characteristics of the selected study were extracted in a table including year of publi-cation, study design, number of studies, and regimens for the treatment. We included results evaluating the efficacy of drugs in patients with at least one of the clinical assessment scales: 1) Alzheimer’s Disease Assessment Scale–cognitive subscale (ADAS-cog), 2) Mini-Mental State Examination (MMSE), 3) Neuropsychiatric Inventory (NPI), 4) Clinical Dementia Rating scale (CDR), Clinical Global Impression of Change (CGIC) or Clinician’s Interview-Based Impression of Change plus caregiver’s input (CIBIC+), 5) Progressive Deterioration Scale (PDS), Gottfries Bråne Steen (GBS), Disability Assessment for Dementia (DAD) or Activities of Daily Living (ADL), 6) incidence of adverse events. The selection of assessments was extracted on study size, sample size, mean difference (Fixed, 95% CI) or odds ratio (Fixed, 95% CI), and heterogeneity (I²). A percentage of 0–25% was classified as mild, 26–50%, as moderate, and 51–75%, as significant between-study heterogeneity. If I² > 50%, a random-effects model was used for the analysis, or the data was analyzed on fixed-effects model [15].

Statistical analysis

The sample size and mean difference were used to calculate the four clinical assessment scales. MMSE/ADAS-cog scores were used to evaluate cognitive functions, behavioral symptoms in patients were calculated by NPI. We focused on the CIBIC+ or CGIC as global assessment of change; PDS, GBS, DAD, and ADL as activities of daily living. The adverse events were assessed incidence of adverse events, and the OR were calculated. Therefore, mean difference or odds ratio with 95% CI and p values were used to assess the efficacy and safety of the study medications.

RESULTS

Literature search and study selection

Through the initial search, we retrieved a total of 2,853 records from PubMed, Web of science, Coch-rane Library, and Embase. After examining the titles and abstracts, 112 studies were selected for further full-text scrutiny. In all, 96 studies were excluded due to the following reasons: samples overlap with other studies (n = 39), no necessary sample data (n = 21), other outcomes (n = 12), other dementia (n = 11), other language (n = 5), no placebo group (n = 4), mild cognitive impairment (n = 4) (Fig. 1). Thus, 16 studies were included in the umbrella review: Birks and Harvey (2018) [16], Jiang et al. (2015) [17], Birks et al. (2015) [18], Jiang and Jiang (2015) [19], Gauthier et al. (2015) [20], Sun et al. (2012) [21], Chau et al. (2015) [22], Li et al. (2008) [23], Liu and Wang (2019) [24], Matsunaga et al. (2019) [25], Lu et al. (2020) [26], Avgerinos et al. (2020) [27], Burckhardt et al. (2020) [28], Abushouk et al. (2017) [29], Liao et al. (2020) [30], Xuan et al. (2020) [31]. The main characteristics and the quality scores of the included studies are shown in Table 1.

Fig. 1

Literature review flowchart.

Table 1

Description and AMSTAR scores of included studies

Study	Conditions	Studies Included	Study duration (median, range)	Daily dose (median, range)	Outcomes	AMSTAR scores	Study quality
Birks and Harvey (2018) [16]	Donepezil versus Placebo	30	24W (12–60W)	10 mg/d (1–23 mg/d)	1. MMSE 2. ADAS-cog 3. NPI 4. CIBIC-plus or CGIC 5.ADL	9/11	High
Jiang et al. (2015) [17]	Galantamine versus Placebo	11	12W (8–28W)	24 mg/d (16–40 mg/d)	1. MMSE 2. ADAS-cog 3. NPI 4. CIBIC 5. ADL	11/11	High
Birks et al. (2015) [18]	Rivastigmine versus Placebo	13	26W (13–52W)	6 mg/d (1–12 mg/d)	1. MMSE 2. ADAS-cog 3. NPI 4. CIBIC-plus 5. PDS	8/11	High
Jiang and Jiang (2015) [19]	Memantine versus Placebo	13	24W (12–52W)	10 mg/d (10–28 mg/d)	1. MMSE 2. NPI 3. CIBIC-plus 4. ADL	10/11	High
Gauthier et al. (2015) [20]	Cerebrolysin versus Placebo	6	26W (4–26W)	30 ml/d	1. MMSE 2. ADAS-cog 3. CGIC or CIBIC 4. ADL	7/11	Medium
Sun et al. (2012) [21]	Atorvastatin versus Placebo	2	30W (8–52W)	80 mg/d	1. MMSE 2. ADAS-cog 3.NPI 4. CGIC	10/11	High
Chau et al. (2015) [22]	Latrepirdine versus Placebo	7	26W to 52W	10 mg to 20 mg PO TID	1. MMSE 2. ADAS-cog 3. NPI 4. CIBIC-Plus 5.ADL	10/11	High
Li et al. (2008) [23]	Huperzine A versus Placebo	6	12W (8–36W)	0.3 mg/d	1. MMSE 2. ADAS-cog 3. CDR 4. ADL	9/11	High
Liu and Wang (2019) [24]	IVIG versus Placebo	5	24W (8–78W)	0.4 g/kg	1. MMSE 2. ADAS-cog	10/11	High
Matsunaga et al. (2019) [25]	Idalopirdine versus Placebo	4	18W (12–18W)	45 mg/d	1. ADAS-cog	9/11	High
Lu et al. (2020) [26]	Anti-Aβ agents versus Placebo	19	72W (4–104W)	NA	1. MMSE 2. ADAS-cog 3. CDR 4. ADL	10/11	High
Avgerinos et al. (2020) [27]	Medium Chain Triglycerides versus Placebo	8	13W (3–26W)	20 gr/d (20–56 gr/d) or 42.5 ml/d (22.5–165 ml/d)	1. MMSE 2. ADAS-cog	10/11	High
Burckhardt et al. (2020) [28]	Souvenaid versus Placebo	3	53W	125 ml/d	1. ADAS-cog 2. CDR 3. ADL	10/11	High
Abushouk et al. (2017) [29]	Bapineuzumab versus Placebo	6	78W (52–78W)	1.0 mg/kg (0.15–2 mg/kg)	1. MMSE 2. ADAS-cog 3. CDR 4. DAD	10/11	High
Liao et al. (2020) [30]	Ginkgo biloba versus Placebo	7	12W to 26W	240 mg/d (120–240 mg/d)	1. ADAS-cog 2. CIGC 3. ADL, GBS	10/11	High
Xuan et al. (2020) [31]	Statins versus Placebo	9	53W (12–78W)	Atorvastain: 20 mg/d (20–80 mg/d), Simvastatin: 40 mg/d (20–80 mg/d)	1. MMSE 2. ADAS-cog 3. NPI 4. ADL	9/11	High

As shown in Table 1, a total of 149 clinical trials were included, with 16 drug therapies in the treatment groups. All studies were randomized controlled clinical trials, and the treatment duration ranged from 3 to 104 weeks. All meta-analyses included were of high quality according to AMSTAR score.

Cognitive functions

From our search, 15 studies included the mean change on the effect of the medications in the ADAS-Cog score from baseline (Table 2). Seven studies (46.7%) including Donepezil (MD: –2.35, 95% CI –2.82 to –1.89), Galantamine (MD: –2.3595, 95% CI –3.32 to –2.57), Rivastigmine (MD: –1.57, 95% CI –1.96 to –1.17), Cerebrolysin (MD: –2.33, 95% CI –3.35 to –1.31), Latrepirdine (MD: –0.68, 95% CI –1.25 to –1.10), Huperzine A (MD: –5.36, 95% CI –7.08 to –3.64), and Ginkgo biloba (RR: 1.57, 95% CI 1.30 to 1.91) showed better outcomes for cognitive function compared to placebo. Moreover, only 194 participants were included in one study on Huperzine-A treatment at 12 weeks. Risk ratio, 95% CI was used to assess the effect of Ginkgo biloba in cognitive function. Eight studies (53.3%) indicated no significant difference in effectiveness as compared to placebo.

Table 2

Results of pairwise meta-analyses for ADAS-cog

		Pairwise meta-analyses
Comparative medications	Reference medications	Number of studies	Number of patients	MD/RR	95% CI	I²	p
Donepezil	Placebo	8	2,219	–2.35	[–2.82, –1.89]	13	< 0.00001
Galantamine	Placebo	11	3,989	–2.95	[–3.32, –2.57]	12	< 0.00001
Rivastigmine	Placebo	8	3,744	–1.57	[–1.96, –1.17]	73	< 0.00001
Cerebrolysin	Placebo	4	494	–2.33	[–3.35, –1.31]	37	< 0.00001
Latrepirdine	Placebo	3	1,243	–0.68	[–1.25, –1.10]	88	0.02
Huperzine A	Placebo	1	194	–5.36	[–7.08, –3.64]	NA	< 0.00001
Atorvastatin	Placebo	2	660	–0.22	[–1.12, 0.67]	83	0.62
IVIG	Placebo	4	579	–0.16	[–0.54, 0.22]	0	0.41
Idalopirdine	Placebo	4	2,746	–0.26	[–0.75, 0.23]	62	0.29
Anti-Aβ agents	Placebo	15	10,041	0.17	[0.15, 0.19]	100	0
Medium Chain Triglycerides	Placebo	3	422	–0.54	[–1.24, 0.16]	0	0.39
Souvenaid	Placebo	1	428	1.02	[–1.11, 3.15]	NA	0.35
Bapineuzumab	Placebo	4	2,449	0.14	[–0.72, 0.99]	25	0.75
Statins	Placebo	5	1,233	–0.16	[–2.67, 2.36]	80.1	0
Ginkgo biloba	Placebo	4	NA	1.57	[1.30, 1.91]	52.4	0.050

CI, confidence interval; MD, mean difference; RR, risk ratio; I², heterogeneity; IVIG, Intravenous immunoglobulins.

As the results of statistics (Table 3) showed on the cognition for MMSE. Five studies (38.5%) revealed that Donepezil (MD: 1.08, 95% CI 0.79 to 1.37), Galantamine (MD: 2.5, 95% CI 0.86 to 4.15), Rivastigmine (MD: 0.55, 95% CI 0.34 to 0.77), Huperzine A (MD: 2.81, 95% CI 1.87 to 3.76), and Statins (MD: 1.09, 95% CI 0.00 to 2.18) led to significantly greater improvement than placebo. The other treatments indicated no significant difference in effectiveness as compared to placebo.

Table 3

Results of pairwise meta-analyses for MMSE

		Pairwise meta-analyses
Comparative medications	Reference medications	Number of studies	Number of patients	MD	95% CI	I²	p
Donepezil	Placebo	9	2,115	1.08	[0.79, 1.37]	0	< 0.00001
Galantamine	Placebo	4	224	2.5	[0.86, 4.15]	0	0.003
Rivastigmine	Placebo	8	3,755	0.55	[0.34, 0.77]	22	< 0.00001
Huperzine A	Placebo	4	220	2.81	[1.87, 3.76]	52	< 0.00001
Statins	Placebo	9	1,489	1.09	[–0.00, 2.18]	88	0.000
Cerebrolysin	Placebo	2	333	–0.6	[–1.28, 0.08]	20	0.08
Memantine	Placebo	5	1,104	0.42	[–0.10, 0.94]	29	0.12
Atorvastatin	Placebo	2	677	0.77	[–0.57, 2.10]	69	0.26
Latrepirdine	Placebo	3	1,243	0.59	[–0.94, 2.11]	92	0.45
IVIG	Placebo	3	120	0.05	[–1.82, 1.93]	26	0.95
Anti-Aβ agents	Placebo	8	6,210	–0.29	[–0.76, 0.17]	100	< 0.00001
Medium Chain Triglycerides	Placebo	4	222	–0.29	[–0.55, 0.03]	0	0.965
Bapineuzumab	Placebo	5	1,412	0.08	[–0.31, 0.47]	0	0.68

CI, confidence interval; MD, mean difference; I², heterogeneity; IVIG, Intravenous immunoglobulins.

Behavioral symptoms

Table 4 presents the results of the comparisons of behavioral symptoms; a total of 7 studies were asse-ssed by NPI scores. Patients treated with Galantamine (MD: –1.58, 95% CI: –0.54 to –0.62), Memantine (MD: –1.62, 95% CI: –2.68 to –0.56), and Latre-pirdine (MD: –1.77, 95% CI: –3.09 to –0.45) showed better behavioral symptoms than those administered with placebo. There was no difference among Don-epezil (MD: –1.62, 95% CI: –3.43 to 0.19, p = 0.08), Rivastigmine (MD: –0.06, 95% CI: –0.20 to 0.09, p = 0.42), Atorvastatin (MD: 2.07, 95% CI: –1.59 to 5.73, p = 0.27), Memantine (MD: –0.29, 95% CI: –1.23 to 0.66, p = 0.55), or Statins (MD: –1.16, –1.88 to –0.44) and placebo.

Table 4

Results of pairwise meta-analyses for NPI

		Pairwise meta-analyses
Comparative medications	Reference medications	Number of studies	Number of patients	MD	95% CI	I²	p
Galantamine	Placebo	4	1,918	–1.58	[–2.54, –0.62]	0	0.001
Memantine	Placebo	8	2,839	–1.62	[–2.68, –0.56]	63	0.003
Latrepirdine	Placebo	3	1,243	–1.77	[–3.09, –0.45]	32	0.009
Donepezil	Placebo	4	1,035	–1.62	[–3.43, 0.19]	71	0.08
Rivastigmine	Placebo	2	744	–0.06	[–0.20, 0.09]	0	0.42
Atorvastatin	Placebo	2	577	2.07	[–1.59, 5.73]	77	0.27
Statins	Placebo	4	1,189	–1.16	[–1.88, –0.44]	45.4	0.139

CI, confidence interval; MD, mean difference; I², heterogeneity.

Global clinical assessment

The effects of the medications on clinical global change were assessed by the CIBIC-plus, CGIC, and CDR (Table 5). Eight studies (61.5%) showed that Donepezil (OR: 2.00, 95% CI: 1.69 to 2.37), Galantamine (OR: 1.48, 95% CI: 1.27 to 1.73), Cerebrolysin (OR: 3.08, 95% CI 2.28 to 4.18), Memantine (MD: –0.17, 95% CI: –0.15 to –0.04), Latrepirdine (MD: –0.60, 95% CI –0.89 to –0.31), Huperzine A (MD: –0.80, 95% CI –0.95 to –0.65), Anti-Aβ agents (MD: 0.25, 95% CI –0.03 to 0.52), and Souvenaid (MD: –0.56, 95% CI –0.95 to 0.17) probably result in little or no difference in the clinical global change score. Patients with Atorvastatin (MD: 0.13, 95% CI: –0.15 to 0.40, p = 0.38) and Bapineuzumab (MD: 0.21, 95% CI: –0.07 to 0.49, p = 0.14) experienced no difference compared to placebo. In contrast, Rivastigmine (OR: 0.65, 95% CI: 0.54 to 0.79) showed no change or a deterioration. In addition, 183, 65, and 230 participants were included in one study on Latrepirdine, Huperzine-A, and Souvenaid treatment respectively.

Table 5

Results of pairwise meta-analyses for CGIC

		Pairwise meta-analyses
Comparative medications	Reference medications	Number of studies	Number of patients	OR/MD	95% CI	I²	p
Donepezil	Placebo	10	2,947	2.05	[1.72, 2.44]	30	< 0.00001
Galantamine	Placebo	8	3,551	1.48	[1.27, 1.74]	22	< 0.00001
Rivastigmine	Placebo	7	2,389	0.65	[0.54, 0.79]	17	< 0.00001
Cerebrolysin	Placebo	6	772	3.08	[2.28, 4.18]	55	< 0.00001
Memantine	Placebo	6	2,445	–0.17	[–0.29, –0.04]	0	0.008
Atorvastatin	Placebo	2	677	0.13	[–0.15, 0.40]	52	0.38
Latrepirdine	Placebo	1	183	–0.60	[–0.89, –0.31]	NA	< 0.0001
Huperzine A	Placebo	1	65	–0.80	[–0.95 –0.65]	NA	< 0.00001
Anti-Aβ agents	Placebo	9	7,306	0.25	[–0.03, 0.52]	100	< 0.00001
Souvenaid	Placebo	1	230	–0.56	[–0.95 –0.17]	NA	0.005
Bapineuzumab	Placebo	3	2,230	0.21	[–0.07 –0.49]	0	0.14
Ginkgo biloba	Placebo	3	NA	3.12	[2.21, 4.41]	31.1	0.234

CI, confidence interval; OR, odds ratio; MD, mean difference; I², heterogeneity.

Adverse events

The meta-analysis of participants with at least one adverse event indicated a beneficial effect in favor of placebo treatment compared with Donepezil (OR: 1.53, 95% CI: 1.30 to 1.80), Galantamine (OR: 1.95, 95% CI: 1.51 to 2.52), Rivastigmine (OR = 1.87, 95% CI: 1.97 to 2.81), Atorvastatin (OR: 1.15, 95% CI: 1.05 to 2.01), and Bapineuzumab (RR = 1.31, 95% CI: 1.18 to 1.45) treatment. The adverse events resulting from administration of other treatments were mild, and there were no significant differences in adverse events between these groups and placebo groups (Table 6).

Table 6

Results of pairwise meta-analyses for Adverse events

		Pairwise meta-analyses
Comparative medications	Reference medications	Number of studies	Number of patients	OR/RR	95% CI	I2	p
Donepezil	Placebo	13	3,518	1.53	[1.30, 1.80]	0	< 0.00001
Galantamine	Placebo	16	4,963	1.95	[1.51, 2.52]	64	< 0.00001
Rivastigmine	Placebo	7	3,210	1.87	[1.12, 3.12]	89	0.02
Atorvastatin	Placebo	2	702	1.15	[1.05, 2.01]	63	0.02
Bapineuzumab	Placebo	6	NA	1.31	[1.18, 1.45]	77.8	< 0.00001
Memantine	Placebo	13	4,101	0.92	[0.78, 1.08]	22	0.32
Latrepirdine	Placebo	4	1,034	1.09	[0.85, 1.40]	45	0.51
Huperzine A	Placebo	1	202	1.02	[0.20, 5.18]	NA	0.98
IVIG	Placebo	5	755	1.03	[0.71, 1.48]	0	0.89
Souvenaid	Placebo	1	524	0.9	[0.78, 1.03]	NA	0.12
Statins	Placebo	6	1,272	0.72	[0.49, 1.06]	30.9	0.204
Ginkgo biloba	Placebo	5	NA	0.92	[0.84, 1.00]	0	0.776
Rivastigmine	Placebo	7	3,587	2.47	[1.73, 3.53]	70	< 0.00001

CI, confidence interval; OR, odds ratio; RR, risk ratio; I², heterogeneity; IVIG, Intravenous immunoglobulins.

DISCUSSION

Our umbrella review was conducted on the data derived from treatments for AD patients in which was used to appraise the relative effectiveness and safety of therapy. We attempted to summarize data from published systematic reviews and meta-analyses to indicate that there are significant beneficial treatments in patients with AD. Our study showed that AChE inhibitors (donepezil, galantamine, rivastigmine, Huperzine A), Ginkgo biloba, and cerebrolysin appear to be beneficial for cognitive and global performances and activities of daily living in patients with AD. Memantine appears to be a safe and tolerable drug for moderate to severe AD patients. Atorvastatin, latrepirdine, IVIG, anti-Aβ, Medium Chain, Souvenaid, and bapineuzumab may have no important impact on slowing cognitive or functional decline. In addition, Memantine, Latrepirdine, Huperzine A, IVIG, Souvenaid, Statins, and Ginkgo biloba show no serious adverse events in AD patients. Our results need to be interpreted with caution to determine the optimal treatment strategy for AD patients.

The effects of AChEIs may be considerable for AD, which is incurable with current treatment paradigms, but other medications that may slow down the progression of AD patients are worth exploring. Previous studies showed that AChEIs have beneficial effects on cognitive function of AD patients [32, 33], while one study demonstrated the galantamine performed the best [34]. Our results indicated that all AChEIs were more effective for improving cognitive function compared to placebo. Researches have demonstrated that there was a slightly higher effect of memantine observed for the severe cases of AD than that observed for the mild to moderate AD patients [35]. Similar to these studies, memantine treatment showed statistically significant improvement of cognition compared to placebo in our study. Unfortunately, the lack of placebo controls for studies with MMSE may limit the speculation in this study. In addition, cerebrolysin treatment showed effects in the ADAS-Cog scale and was recommended by FDA [36]. Moreover, we considered the treatment with atorvastatin, latrepirdine, IVIG, Anti-Aβ agents, Medium Chain Triglycerides, Souvenaid, Bapineuzumab, and Statins to have no effect on cognitive function because of higher heterogeneity or p > 0.05. AD is a progressive disease, however, our study mainly selected clinical studies to demonstrate short-term efficacy on cognition. Although long-term clinical trials are ethically questionable, long-term trials with high-quality are essential to indicate comparative differences between treatments of AD.

The behavioral symptoms of patients with AD are often evaluated by NPI, which assesses the severity and frequency of neuropsychiatric symptoms. Patients with AD deteriorate progressively with varying degrees of severity of disease, which may affect the results obtained from pooling data. As a result, previous meta-analyses have reported that the efficacy of AChEIs may be related to the severity of dementia [37]. In addition, latrepirdine was reported as only a modest but significant effect found on behavior in AD patients [38]. Therefore, recent meta-analyses extracted included varying degrees of AD, so there was no evidence if donepezil treatment exhibited a preferable improvement on neuropsychiatric symptoms [16]. Our study suggested that atorvastatin and statins were not particularly effective for improvement of neuropsychiatric symptoms of AD. In addition, a modest and better effect on behavioral symptoms was found for galantamine and latrepirdine [34]. Our study suggested that the clinical manifestations of patients with AD on neuropsychiatric symptoms are varied when the severity and symptoms characteristic of dementia are not optimally controlled. The heterogeneity may lead to inconsistencies in the results of each trial and combined analysis of drug treatment. In order to verify the efficacy of the treatment on neuropsychiatric symptoms, further studies are needed for individual psychiatric symptoms.

Previous meta-analyses have demonstrated that patients treated with donepezil and galantamine provided a modest and better improvement in global clinical change, while treatment with rivastigmine showed no change or a deterioration [18 , 40]. In addition, cerebrolysin shows statistically significant advantage compared to placebo the short-term and long-term analysis. Although Latrepirdine, Huperzine A, and bapineuzumab treatment contains only one trial, they show a modest and better effect. Moreover, the global scores of atorvastatin and ginkgo biloba trials did not change. Studies have shown that the response rate of global clinical change assigned to placebo is positively correlated with the implementation time [37]. We believe that further analyses are needed to clarify the factors associated with the increased placebo effect over time in global clinical trials.

In the treatment of AD, the safety of the treatments is critical since they should be taken on a long-term basis. The number of participants with at least one serious adverse event such as nausea, diarrhea, cardiovascular events, gastrointestinal symptoms, and other kinds of disorders were extracted. The incidence of withdrawals due to adverse events with donepezil, rivastigmine, and galantamine treatments in the present review tended to be higher than placebo groups [41]. Furthermore, previous clinical trials reported that compared to rivastigmine and galantamine, donepezil showed a more advantageous tolerability profile [42]. The novel alkaloid Huperzine-A performed well for mild severity cases and for brief therapeutic duration, which was confirmed in previous review [43]. Moreover, our study summarized that memantine, latrepirdine, IVIG, Souvenaid, statins, and ginkgo biloba were both safe and well tolerated.

In recent years, Aβ-targeting agents as a treatment to investigate for mild to moderate AD patients has been a potential disease-modifying therapy [44]. A previous study has shown that anti-Aβ agent, Donanemab, results in a better beneficial effect for cognition and activities of daily living, and shows a modified form of deposited Aβ plaques [45]. In this study, none of the anti-Aβ agents have showed effective for cognitive or functional decline. Well-designed RCTs are necessary to explore the benefit of anti-Aβ agents as treatment in patients with AD, and further research on Aβ clearance should be carefully explored.

In general, the treatment for patients with AD is aimed at promoting independence, maintaining function, and treating symptoms. Previous meta-analyses and reviews have focused on the possible effectiveness and safety of AChEIs and memantine [39 , 46–48], even though many patients experience modest efficacy and many adverse events with the treatment. As a result, we need to identify an efficacious and safe treatment paradigm for AD patients. Studies have shown that Huperzine-A improved cognitive function, and the adverse effects were mild for the treatment of AD [23]. However, larger sample size and long-term follow-up studies are needed to find the reliability of this medication. Due to its efficacy in improving cognitive ability, we believe that Huperzine-A can be employed as first-line treatment.

Limitations

The limitation of this study needs to be acknowledged. First, there was relatively small direct comparative evidence of treatments for AD patients in our included studies. Second, there may be other factors that may lead to the umbrella review inconsistencies, such as the duration and quality of the study. Furthermore, a considerable number of studies do not have the abovementioned data, which makes less studies available.

Conclusion

In conclusion, our study suggested that AChE inhibitors, Ginkgo biloba, and cerebrolysin are the optimum cognitive and activities of daily living medication for patients with AD. In the future, the combination of well tolerated agents and other significant beneficial treatments should be used for patients with AD, which will contribute to the successful construction of similar study.

Footnotes

ACKNOWLEDGMENTS

This study was supported by the National Natural Science Foundation of China (81703492), Beijing Natural Science Foundation (7182092), the Minzu University Research Fund (2018CXTD03) and the MUC 111 project.

Authors’ disclosures available online ().

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