Abstract
Background: Alzheimer’s disease (AD) is the most common cause of dementia worldwide. Despite the publication of numerous systematic reviews and meta-analyses that have summarized the evidence associated with pharmacotherapies (PTs) and non-pharmacotherapies (NPTs) for the wide range of interventions available for AD treatment, the implementation of PTs and NPTs in the real-world practice is limited. Due to PTs have frequent adverse reactions causing poor drug adherence and NPTs have various approaches which result in difficult to get accessed by the AD patients. Additionally, their comparative safety and efficacy remains insufficiently defined. Methods: The systematic reviews of randomized controlled trials (RCTs) and meta-analysis (MA) is identified through PubMed and Scopus from March 2021 to December 2022. The RCTs are selected according to the following criteria: conducted in elderly patients aged 60 years or older with AD living in community or institutionalized settings, applied pairwise meta-analysis (PMA) or network meta-analysis (NMA) approaches providing pooled relative treatment effects for at least one pair of PTs or NPTs, and providing at least one of the following outcomes for patients/caregivers: cognitive, functional status, behavior, quality of life and caregiver stress or burden. We used Revised Cochrane Risk-of-bias tool for Randomized Trials (RoB2) to assess quality and risk of bias in all articles by two dependent reviewers. The two stage NMA is performed and relative treatment effects e.g. standardized mean differences (SMD), unstandardized mean differences (UMD), odd ratios (OR) or relative risks (RR) and variance will be estimated for individual RCTs and pooled across RCTs using STATA 17 Results: Of 2,060 citations of systematic review and MA screened, 282 studies (37,399 people with AD) were included. In the NMA of PTs, PTs+NPTs (122 studies; 26,977 people with AD) found that donepezil+cognitive training (CT) Mini-mental state Examination (MMSE): mean differences (MD) = 5.56 [95% confidence interval (CI) = 4.05, 7.06], Huperzine-A (4.00, 95% CI =1.48, 6.52), Memantine+huperzine (2.58, 95%CI = 1.24, 3.92) improved cognition more than placebo. NMA also found rivastigmine+cognitive stimulation (CS) Neuropsychiatric inventory: MD = -11.54 (95%CI = -18.70, -4.37), Gingo biloba extract (Egb761) (-7.36, 95%CI = -10.64, -4.08), donepezil+memantine (-4.86, 95%CI = -9.42, -0.29) improved behavior more than placebo. The combination of PTs and NPTs; Rivastigmine+CS (MD = 0.92, 95%CI 0.39, 1.44) were also significant interventions that improve functional status (ADL) more than placebo. Regarding to the NMA of NPTs (160 studies; 10,422 people with AD) found that non-invasive brain stimulation (MMSE: MD= 2.45, 95%CI = 1.04, 3.86), CT (1.89, 95%CI = 1.00, 2.78), exercise (1.77, 95%CI = 0.44, 3.10) improved cognition more than usual care. In addition, exercise was associated with functional outcome improvement (0.93, 95%CI = 0.18, 1.68), reducing behavioral problems (-4.52, 95%CI = -8.37, 0.67), and caregiver stress (SMD = -0.69, 95% = -1.28, -0.09) comparing to usual care. NMA of NPTs also discovered that occupational therapy (OT) is the most efficacious to reduce behavior problems (MD = -11.04, 95%CI = -18.82, -3.25) and improve the quality of life (QOL) in AD patients (SMD = 1.00, 95%CI = 0.41, 1.59). Conclusion: In this systematic review and NMA, pharmacotherapies combined with non-pharmacotherapies were found to be most efficacious for improving cognition, functional status and reducing behavior problems in people with AD. The policy makers can support AD patients, caregivers and clinicians in developing health services that enable implementation of NPTs such as exercise, occupational therapy, cognitive training, and cognitive stimulation.
