Article Text

Supplements for cognitive ability in patients with mild cognitive impairment or Alzheimer’s disease: a protocol for systematic review and network meta-analysis of randomised controlled trials
  1. Xin-Yue Zhang1,2,
  2. Ya-Qin Li1,2,
  3. Zi-Han Yin1,2,
  4. Qiong-Nan Bao1,2,
  5. Man-Ze Xia1,2,
  6. Zheng-Hong Chen1,2,
  7. Wan-Qi Zhong1,2,
  8. Ke-Xin Wu1,2,
  9. Jin Yao1,2,
  10. Fan-Rong Liang1,2
  1. 1Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China
  2. 2Acupuncture Clinical Research Center of Sichuan Province, Chengdu, China
  1. Correspondence to Dr Fan-Rong Liang; acuresearch{at}


Introduction Considering the increasing incidence of Alzheimer’s disease (AD) and mild cognitive impairment (MCI) worldwide, there is an urgent need to identify efficacious, safe and convenient treatments. Numerous investigations have been conducted on the use of supplements in this domain, with oral supplementation emerging as a viable therapeutic approach for AD or MCI. Nevertheless, given the multitude of available supplements, it becomes imperative to identify the optimal treatment regimen.

Methods and analysis Eight academic databases and three clinical trial registries will be searched from their inception to 1 June 2023. To identify randomised controlled trials investigating the effects of supplements on patients with AD or MCI, two independent reviewers (X-YZ and Y-QL) will extract relevant information from eligible articles, while the risk of bias in the included studies will be assessed using the Rob 2.0 tool developed by the Cochrane Collaboration. The primary outcome of interest is the overall cognitive function. Pair-wise meta-analysis will be conducted using RevMan V.5.3, while network meta-analysis will be carried out using Stata 17.0 and ADDIS 1.16.8. Heterogeneity test, data synthesis and subgroup analysis will be performed if necessary. The GRADE system will be employed to assess the quality of evidence. This study is scheduled to commence on 1 June 2023 and conclude on 1 October 2023.

Ethics and dissemination Ethics approval is not required for systematic review and network meta-analysis. The results will be submitted to a peer-reviewed journal or at a conference.

Trial registration number PROSPERO (CRD42023414700).

  • Aged
  • Dementia

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  • To explore the most appropriate supplements for the treatment of Alzheimer’s disease (AD) or mild cognitive impairment (MCI) and to provide the clinical reference for health policy decision-makers.

  • The systematic review will be conducted following the Preferred Reporting Items for Systematic Reviews and Network Meta-Analysis (PRISMA-NMA) and A Measure Tool to Assess Systematic Reviews-2 guidelines.

  • This study will employ strict inclusion and exclusion criteria to search for randomised controlled trials in eight academic databases and three clinical trial registries.

  • To guarantee the inclusion of all relevant studies and mitigate the risk of personal bias, two reviewers will independently perform the study selection, data extraction and quality assessment.

  • Owing to resource limitations, selected studies will be limited to those publically available in Chinese and English languages; therefore, the possibility of language bias cannot be excluded.


As a result of the significant demographic shift towards an ageing population, Alzheimer’s disease (AD) constitutes a prominent challenge within the healthcare system in the 21st century.1 Extensive research has demonstrated that the annual impact of AD on individuals, families and economies amounts to a staggering $1 trillion in global losses, with projections indicating a potential 152 million patients with AD worldwide by 2050.2 AD primarily manifests through a range of clinical symptoms, encompassing cognitive, functional and behavioural impairments.3 Furthermore, mild cognitive impairment (MCI) serves as an intermediary clinical stage situated between physiological ageing and the onset of dementia.4 5 The clinical manifestation of MCI primarily involves cognitive impairment.6 Notably, elderly individuals with MCI are highly susceptible to developing AD. However, it is universally acknowledged that there is no definitive cure for AD and MCI, with most available treatments only capable of alleviating symptoms.7 8 At present the clinical management of AD typically involves the administration of acetylcholinesterase inhibitors (eg, donepezil, galantamine) or N-methyl-D-aspartate receptor antagonists (eg, memantine), which exert adverse effects such as gastrointestinal discomfort and headache.9 Furthermore, there remains a dearth of pharmacological interventions that effectively control MCI in the clinical setting. At present, existing medications not only fail to effectively manage MCI10 but also are associated with the risk of adverse reactions such as nausea, diarrhoea and vomiting.

Consequently, several studies have attempted to identify treatment methods that are both efficacious and safe. Previous studies have consistently documented a correlation between cognitive decline and deficiencies in vitamins,11 12 minerals,13 14 fatty acids,15 coenzyme Q1016 and essential elements. Furthermore, ongoing research is investigating the intricate mechanisms through which supplements enhance cognitive function. Earlier studies have established that fatty acids, minerals and vitamins play a significant role in modulating inflammation, oxidative stress, neurogenesis and neuronal connectivity, all of which are closely associated with brain function.17 18 Meanwhile, previous systematic reviews have demonstrated that selenium supplementation can effectively enhance cognitive scale scores and alleviate certain symptoms associated with AD and MCI.19 Moreover, a systematic review conducted by Gil Martínez et al20 revealed that multivitamin B supplementations, particularly folic acid, confer a beneficial impact in delaying and preventing cognitive decline. Additionally, a large number of clinical trials have been collected to investigate the benefits of various supplements in individuals with MCI or AD. For instance, Tamtaji et al21 discovered that cognitive function in patients with AD improved following a 12-week intervention involving probiotics and selenium. Likewise, Chen et al22 observed that individuals with AD who received folic acid and vitamin B12 supplementation exhibited higher Montreal Cognitive Assessment (MOCA) scores compared with those in the placebo group. Similarly, Stavrinou et al23 determined that the administration of high doses of omega-3 and omega-6 fatty acids, along with antioxidant vitamins, enhanced cognitive function in patients with MCI.

Oral supplementation has been proposed as a potentially viable therapeutic approach for AD or MCI. However, existing systematic reviews and meta-analyses have primarily examined a limited range of supplements24 25 or have solely employed traditional meta-analytic techniques. Consequently, the identification of the most efficacious supplements for the treatment of AD or MCI remains elusive. Network meta-analysis (NMA), a statistical methodology that integrates both direct and indirect evidence from multiple trials, offers a means to rank various interventions more accurately.26 By employing NMA, decision-makers in clinical practice can gather more reliable evidence to inform their selection of the optimal treatment. To identify optimal supplements for patients with AD or MCI, this study aims to perform an NMA to compare and rank various supplementations for the treatment of patients with AD or MCI.


The purpose of this study is to identify ideal supplements for the treatment of AD or MCI and to provide a clinical reference for health policy decision-makers.

Methods and analysis

This study protocol has been registered on PROSPERO (registration number CRD42023414700). The protocol will adhere to the guidelines outlined in the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocol (PRISMA-P)27 (online supplemental material 1). The systematic review will be conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Network Meta-Analysis (PRISMA-NMA) and A Measure Tool to Assess Systematic Reviews-2 guidelines.28 29 This study is scheduled to commence on 1 June 2023 and conclude on 1 October 2023. Only randomised controlled trial (RCT) data from the database will be used with no direct participation of patients.

Patient and public involvement

Patients and/or the public were not involved in the design, conduct, reporting or dissemination plans of this research.

Eligibility criteria

Types of studies

RCTs of AD or MCI supplement therapy will be considered regardless of language or publication type.

Types of participants

The diagnostic criteria for AD comprise internationally recognised criteria such as DSM-IV or DSM-V30 31 and ICD-10,32 among others. Similarly, the diagnostic methods for mild cognitive impairment (MCI) involve the use of criteria such as Petersen criteria,5 DSM-V criteria,33 NIA-AA criteria34 and other internationally recognised criteria, regardless of the subtype or method of diagnosis. There will be no limitations on participants’ gender, age or ethnicity.

Types of interventions

Supplement interventions such as vitamins,35 minerals,36 fatty acids,37 coenzyme Q10,38 probiotics,39 etc, will be included.

Types of control group

The placebo control group is considered the primary type of control group in this study.

Types of outcome measures

The primary outcome is overall cognitive function, measured using the MOCA. The secondary outcomes are the clinical memory scale and the activities of daily living.

Exclusion criteria

Patients not suffering from AD or MCI2; no intervention with supplements; cognitive function3; no outcome indicators on cognitive function4; non-RCTs, quasi-RCTs, cluster RCTs, animal studies, case studies, qualitative studies, conference abstracts, comments, letters and duplicated articles5; and a lack of research information.

Information sources and search strategy

The following electronic databases will be searched: Chinese Biomedical Literature Database, China National Knowledge Infrastructure, Wanfang Database, VIP Database, Web of Science, Embase, PubMed and the Cochrane Central Register of Controlled Trials. To minimise publication bias, data from clinical registries (WHO ICTRP, and ChiCTR) will be retrieved as well. The retrieval time is from the establishment of the database to 1 June 2023.

The following search terms will be used1: Alzheimer’s Disease, mild cognitive impairment, etc2 (disease); supplement, nutrition, ascorbic acid, calcium, sodium, magnesium, fatty acids, omega 3 polyunsaturated fatty acid, fish oil, coenzyme q10, probiotics, etc (supplement intervention); and3 randomised controlled trials or RCTs (study types). The terms will be used alone or in combination using ‘and’ and ‘or’. The search strategy for PubMed is presented in table 1.

Table 1

Search strategy in PubMed

Study records

Study selection and data extraction

Two independent reviewers (X-YZ and Y-QL) will screen titles, keywords and abstracts for relevance. Duplicate and ineligible studies will be excluded from the review process. All remaining studies will be examined for inclusion once the full text has been reviewed. In case of disagreements, a third reviewer (F-RL or Z-HY) will countercheck and arbitrate.

Two independent reviewers (X-YZ and Y-QL) will extract data using a predesigned extraction form including1 identification information (ie, year, authors and country),2 general information (ie, study design, sample size and allocation ratio),3 participants (ie, gender, age),4 intervention and control groups,5 outcomes and6 main results. The respective authors will be contacted to address any missing data. Figure 1 depicts the study process.

Figure 1

Flow chart of the selection process.

Quality assessment

Two assessors (X-YZ and Y-QL) will independently appraise the quality of the selected RCTs using version 2 of the Cochrane tool for assessing the risk of bias in RCTs (Rob 2.0) from the Cochrane Collaboration.40 The included trials will be rated and classified as low risk, high risk or some concerns. If the risk of all domains is deemed low, the study results will be considered to have an overall low risk of bias. Some concerns reflect some concerns in any domain, while studies will be denoted as high risk of bias if any domain is judged to be at high risk. A third reviewer (F-RL or Z-HY) will be consulted during the final decision-making process.


Data synthesis

Review Manager statistical software (RevMan) V.5.3 will be used for data synthesis and analysis. Pre-post differences for the included RCTs will serve as outcomes.41 In other words, we will focus on the mean and SD of the changes between the results of the supplement intervention and the baseline. All data will be expressed as 95% CI. Mean differences (MDs) will be applied for continuous data. Statistical heterogeneity will be identified and measured using I2 statistics and p-value. The fixed-effects model will be applied if p>0.1 and I2<50%; otherwise, the random effects model will be used.42

Network meta-analysis

Bayesian network meta-analysis (NMA) will be conducted using ADDIS 1.16.8 and Stata 17.0 software to compare the effectiveness of supplement interventions. ADDIS is a network analysis software that uses a Bayesian framework and the Markov chain Monte Carlo (MCMC) method.43 It facilitates prior evaluation and data processing, enabling automatic network meta-analysis of relevant data. Efficacy and adverse reactions will be expressed as odds ratios for count data, while measurement data will be expressed as weighted mean differences. All effect sizes will be reported with a 95% CI. For all data, the node-split model will be initially used for the consistency test. If there is no statistical difference between direct and indirect comparisons (p>0.05), the consistency model will be used. Otherwise, the inconsistency model will be used for analysis.

White44 45 reported that the ‘network’ command will be inputted in Stata 17.0 for data preprocessing, generating network maps and determining the efficacy of intervention measures. In network maps, nodes represent interventions, and each line between two nodes signifies a direct comparison between these two interventions. Studies not connected to the network will be excluded from the network meta-analysis.

Subgroup analysis and sensitivity analysis

Heterogeneity will be considered significant when I2≥50% and p<0.0546 based on the Cochrane Handbook 5.4 guidelines. If there is significant heterogeneity, subgroup analysis will be performed based on the type of intervention (eg, vitamins, minerals, fatty acids, etc). Meanwhile, the sensitivity analysis will be conducted to ensure the accuracy and stability of inferences from our results to mitigate the effects of small sample-sized trials and the high methodological risk of bias.

Dealing with missing data

If the necessary data are insufficient or not provided in the included studies, the reviewers will make efforts to contact the respective authors via email. Should the missing data remain unattainable, those specific studies will be excluded from the analysis.

Assessment of publication bias

If over 10 trials are eventually included, a comparative adjusted funnel plot will be plotted to identify potential publication bias. Ideally, the data of these studies will be represented by symmetrical inverted funnel plots. Conversely, an asymmetric funnel plot indicates publication bias.

Quality of evidence

The Grading of Recommendations Assessment, Development and Evaluation (GRADE) system will be used to assess the quality of evidence47 by two reviewers (X-YZ and Y-QL). Evidence quality will be ranked as ‘high’, ‘moderate’, ‘low’ or ‘critically low’. The assessment results will also be cross-­checked, and disagreements will be adjudicated by a third reviewer (Z-HY).


AD has been recognised by the WHO as a global public health priority. Alois Alzheimer reported the first case in 1907, and the disease is named after him.48 Reisberg et al introduced the term MCI in the late 1980s to describe patients in an intermediate stage between normal cognitive ageing and dementia.49 The NIA-AA diagnostic criteria for AD, revised in 2011, regards MCI as the precursor stage of AD.50 To date, despite a better understanding of the pathogenesis of AD and MCI and the concept of disease, disease-modifying treatments are lacking. Supplements are commonly regarded as safe51 and advantageous for enhancing cognitive capacity among older individuals.52 Deepening the study of supplements may be an important breakthrough in improving cognitive function in patients with AD and MCI.

To the best of our knowledge, the majority of meta-analyses focused on the efficacy of a single supplement intervention or the selection of several types of supplements for research. Consequently, there remains a dearth of comprehensive and robust evidence-based medical data to compare and analyse the most efficacious supplement intervention. Network meta-analysis is a valuable approach for comparing multiple interventions and deriving effectiveness rankings through direct and indirect comparisons.53 Our study aims to employ this methodology, investigate the impact of various supplement interventions on the cognitive function of individuals with AD or MCI and determine their efficacy. Consequently, our research has the potential to identify the most effective supplemental therapy for AD or MCI, thereby providing valuable insights for future research endeavours and clinical practices.

Ethics statements

Patient consent for publication


Supplementary materials

  • Supplementary Data

    This web only file has been produced by the BMJ Publishing Group from an electronic file supplied by the author(s) and has not been edited for content.


  • X-YZ and Y-QL contributed equally.

  • Contributors XZ, Y-qL, Z-HY and F-RL conceived and designed the study. X-YZ and Y-QL wrote the first draft of the current protocol. F-RL and Z-HY provided input to the final draft. Q-NB and M-ZX provided statistical expertise and assisted in the drafting of the manuscript. Z-HC and K-XW drew table 1 and figure 1 and assisted in drafting the manuscript. JY and W-QZ: acquisition of data. All authors wrote the manuscript and approved the submitted version.

  • Funding This work was supported by the National Natural Science Foundation of China (Grant numbers: 81590950) and Chengdu University of Traditional Chinese Medicine.

  • Disclaimer PROSPERO registration will include protocol amendments. We will document and publish any modifications to this protocol along with the results of the systematic review.

  • Competing interests None declared.

  • Patient and public involvement Patients and/or the public were not involved in the design, conduct, reporting or dissemination plans of this research.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.