Comparative Efficacy and Safety of Cholinesterase Inhibitors and NMDA Receptor Antagonists in Alzheimer's Disease: A Systematic Review and Network Meta-Analysis of Randomized Controlled Trials.

INTRODUCTION: The study aims to evaluate and rank cholinesterase inhibitors, the NMDA antagonist memantine, anti-amyloid monoclonal antibodies, and non-drug modalities with respect to cognitive outcomes, functional status, neuropsychiatric symptoms, and tolerability. METHODOLOGY: We registered a protocol in PROSPERO and searched PubMed/MEDLINE, Embase, CENTRAL, Web of Science, trial registries, and gray literature through June 2025. Eligible randomized phase II/III trials in adults with clinically diagnosed AD were screened in duplicate. Data on interventions, comparators, outcomes (e.g., MMSE, ADAS-Cog, CDR-SB), and adverse events were extracted. Risk of bias was assessed using Cochrane RoB 2. A Bayesian random-effects NMA synthesized 125 trials (n > 30,000), estimating standardized Mean Differences (SMDs) with 95% Credible Intervals (CrIs). Heterogeneity (I²) and inconsistency (design-by-treatment, node-splitting) were evaluated. RESULTS: The network was well connected, with low-to-moderate heterogeneity (global I² = 38.5%) and no significant inconsistency (p = 0.48). Cognitive training (SMD = 0.45; 95% CrI 0.30-0.60; SUCRA 92%), aerobic exercise (SMD = 0.55; 95% CrI 0.35-0.75; SUCRA 87%), and galantamine (SMD = 0.40; 95% CrI 0.22-0.58; SUCRA 84%) ranked highest versus placebo. Donepezil (SMD = 0.21; 95% CrI 0.11-0.30; SUCRA 78%) and memantine (SMD = 0.24; 95% CrI 0.13-0.35; SUCRA 72%) showed modest benefits. DISCUSSION: Risk-of-bias ratings were low in 37% of trials, some concerns in 48%, and high in 15%. Subgroup analyses confirmed greater cholinesterase inhibitor efficacy in mild AD and superior memantine effects in moderate-to-severe disease. CONCLUSION: Non-pharmacological interventions demonstrated short-term cognitive benefits primarily in mild Alzheimer's disease populations and should be interpreted as adjunctive symptomatic strategies rather than direct substitutes for pharmacological therapy.