This overview study and NMA update will be conducted in accordance with PRISMA guidelines for network meta-analysis and the protocol was registered with the International Prospective Register of Systematic Reviews (PROSPERO) in February 2021 (registration number CRD42021228245)
Study selection process
Type of study
Systematic reviews of randomized controlled trials (RCTs) will be selected according to the following criteria:
- Conducted in elderly patients aged 60 years or older with AD
- Reported PMA or NMA for pooled relative treatment effects for at least one pair of PTs or NPTs
- Provided at least one of the following outcomes for patients/caregivers: cognitive function status, rate of falls, behavior, QoL.
Individual RCTs included in selected systematic reviews will be re-selected based on the following criteria:
- Undertaken in elderly patients aged 60 years or older with AD
- Compared relative treatment effect of at least one pair of PTs or NPTs
- Provided at least one of the following outcomes for patients/caregivers: cognitive function status, rate of falls, behavior, QoL.
The individual RCTs will be excluded where insufficient data is available for pooling following 2-3 attempts to contact the corresponding author.
Type of Participants
We will include any RCT that included elderly participants aged 60 years or older diagnosed as AD using their country’s standard AD diagnostic criteria, e.g., Diagnostic and Statistical Manual of Mental Disorders (DSM) IV22 or DSM-523 (American Psychiatric Association (APA)), the National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer Disease and Related Disorders Association, and/or National Institute on Aging (NIA) and the Alzheimer’s Association criteria24, and/or the International Working Group, and neuropsychological tests to diagnose AD. We will use the Mini-Mental State Examination (MMSE) or Montreal Cognitive Assessment/Clinical Dementia Rating Scale for additional screening.
Intervention
Interventions of interest include any comparison between individual NPTs and usual/standard care or PTs and placebo or head-to-head comparison between PTs and PTs:
- NPTs
The most common NPTs include CST, CR, MT, CCT, and non-invasive brain stimulation (rTMS) and the following will be considered:
- CST
- CR
- Reminiscence therapy (RMT)
- CCT
- Physical activity (PA)
- Aerobic only
- Non-aerobic
- Combination or multicomponent
- High intensity functional exercise
- Functional-based analysis intervention (behavioral management)
- Occupational therapy- fall prevention program
- Care-giver interventions
- Massage
- Recreation therapy
- MT
- Aromatherapy
- Psychological therapy
- Social intervention
- Multisensory stimulation (MSS or Snoezelen)
- Light therapy
- Art therapy
- Therapeutic touch
- Multicomponent therapy (SONAS)
- Acupuncture
- Non-invasive brain stimulation (rTMS, transcranial direct current stimulation (tDCS))
- Animal assisted therapy (AAT)
- Usual/ standard care
- PTs
- Cognitive enhancer
- Cholinesterase inhibiter (ChEIs); donepezil, galantimine, rivastigmine
- NMDA receptor antagonists; memantine
- Herbs; Huperzia serrate, Gingo biloba extract (EGB 761) Yokukansan (TJ-54), Panax Ginseng, saffron (crocus sativus L.)
- Melatonin
- Placebo
Outcome measure
The outcomes of interest include cognitive function, behavioral and psychological symptoms of dementia (BPSD), QoL, functional status and rate of falls. Cognitive function assessed in the original studies mainly using the Mini-Mental State Examination (MMSE), Alzheimer’s Disease Assessment-Scale Cognitive (ADAS-Cog), Montreal Cognitive Assessment (MoCA), Global Cognitive Functions (e.g., Clock drawing test), Clinical Global Impression of Change (CGIC), Clinician’s Interview-Based Impression of Change (CIBIC), self or caregiver reported functions (caregiver input), Clinical Dementia Rating (CDR). The BPSD were evaluated by neuropsychiatric inventory (NPI), brief psychiatric rating scales and other behavior assessment tools. QoL and functional status were measured by EQ5D, Barthel or modified Barthel index. Rate of falls was the number of reported falls. A fall was defined as “a person unintentionally coming to rest on the ground, floor or other level.” The secondary outcomes include caregiver burden and QoL measured by Zarit burden inventory scale (ZBI) and EQ5D, respectively.
Search strategy
Relevant systematic reviews and meta-analyses will be identified by a single reviewer (CB) from PubMed and Scopus from initiation to January 2021. The search terms and strategies are based on patients (P), interventions/ comparators (I/C), outcomes (O), and study design (S) as follows:
P: “Alzheimer dementia; I/C: donepezil, rivastigmine, galantamine, memantine, huperzine-A, EGb761, Yokukansan (TJ-54), “cognitive stimulation therapy”, “cognitive rehabilitation”, “music therapy”, “physical activity”, “non-invasive brain stimulation”, “non-pharmacological therapy”; O: cognitive, behaviors, function, “quality of life”; S: meta-analysis.
Searches will be updated every 3 months until December 2021.
Data extraction
Data will be extracted independently by two reviewers (CB and WT). Data for systematic reviews will be extracted including systematic review characteristics (pairwise or network meta-analysis), number of RCTs included, number of interventions/comparators, type of outcomes, methods used for pooling relative treatment effects (standardized/unstandardized mean difference (SMD/UMD) for continuous outcomes; ORs, RRs for dichotomous outcomes). The following data will be extracted from individual RCTs: patient characteristics (e.g., age, percentage female, body mass index, diabetes, hypertension, cardiovascular disease status etc.), intervention/comparator, type of outcomes and tool/scale used to determine outcome measures. In addition, data for pooling will be extracted including the number of patients, mean and standard deviation (SD) by intervention groups for continuous outcomes, contingency data of intervention and dichotomous outcomes.
Risk of bias and quality assessment
Risk of bias will be assessed using the Risk of Bias in Systematic Reviews (ROBIS) checklist 25 by two independent reviewers (CB and TA), disagreement will be resolved by a third reviewer (AT). Four domains will be considered including study eligibility criteria, methods used to identify and/or select studies, data collection and appraisal of studies, and synthesis/findings. The result will be graded as low or high risk of bias if there is sufficient information to assess, otherwise, it will be graded as unclear.
Risk of bias of individual RCTs will be assessed using the Revised Cochrane risk-of-bias tool for randomized trials considering the five domains of randomization, deviation from the intended intervention, missing outcome data, outcome measurements, and selection of the reported results. Each domain will be rated as low, some concerns, and high risk according to the risk-of-bias tool algorithm. The RCT will be judged as high risk of bias if at least one domain is rated high risk; low risk of bias if all domains are rated as low risk; otherwise, the RCT will be judged as some concerns. Any disagreement will be resolved by consensus or judgment of a third reviewer (AT).
Data Synthesis
A two-stage NMA will be performed as follows: Relative treatment effects (e.g., SMD, UMD, ln ORs/ln RR) along with variance estimates for individual RCTs. Relative treatment effects will be pooled across RCTs using a consistency model and all possible relative treatment comparisons estimated. Consistency assumptions will be assessed using design-treatment interaction methods with a loop-specific approach to identify inconsistencies, where present. Patient characteristics associated with specific loops will be explored and treatment efficacy ranked for each outcome using surface under cumulative ranking curves (SUCRA). Adjusted funnel plots will assess publication bias.
We will perform subgroup analysis to explore source/s of heterogeneity and inconsistency, and will focus on factors including extreme elderly patients (age 85 years or older), stage of disease as defined by the functional assessment staging test (FAST) criteria26, etc. In addition, a sensitivity analysis will be performed by excluding studies with high risk of bias, very old age, low/high effect size/variance (e.g., 25th or 75th percentile) to determine the robustness of the findings. All analyses will be performed using STATA 16.