Wu_2026_Ageing.Res.Rev_120_103216

OBJECTIVE: To compare the efficacy and safety of pharmacotherapies targeting different pathological pathways in Alzheimer's disease (AD). METHODS: We systematically searched PubMed, Embase, the Cochrane Library, Web of Science, ClinicalTrials.gov, and AlzForum for randomized controlled trials (RCTs) from database inception to August 24, 2025. A random-effects network meta-analysis was then conducted. RESULTS: A total of 75 RCTs involving 68,398 participants were included. For Alzheimer's Disease Assessment Scale-Cognitive subscale, interventions targeting inflammatory pathways (standardized mean difference [SMD] = -0.24, 95% confidence interval [CI]: -0.40 to -0.08) and neurotransmitters (SMD = -0.22, 95% CI: -0.29 to -0.15) were superior to placebo; sensitivity analysis additionally supported interventions targeting the gut-brain axis (SMD = -0.26, 95% CI: -0.51 to -0.01). No significant differences were observed for Clinical Dementia Rating-Sum of Boxes. For Mini-Mental State Examination, interventions targeting neurotransmitters significantly improved scores versus placebo (mean difference [MD] = 0.61, 95% CI: 0.37-0.86). Overall, interventions targeting neurotransmitters, mainly consisting of cholinesterase inhibitors, consistently ranked among the most effective treatments. Compared with placebo, interventions targeting neurotransmitters, amyloid-beta (Abeta), and synaptic plasticity/neuroprotection increased the risk of adverse events; interventions targeting Abeta and synaptic plasticity/neuroprotection also raised the risks of serious adverse events, while the risk of death did not differ significantly. CONCLUSIONS: Pharmacotherapies targeting neurotransmitters, the gut-brain axis, and inflammatory pathways may offer comparatively favorable cognitive benefits in AD. However, variations in safety profiles across intervention classes highlight the need for careful benefit-risk assessment. Given the limited evidence base for certain strategies, further high-quality RCTs are warranted to confirm these findings.