Comparative efficacy and safety of pathway-targeted pharmacotherapies for Alzheimer's disease: A systematic review and network meta-analysis of phase III trials.

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 (Aβ), and synaptic plasticity/neuroprotection increased the risk of adverse events; interventions targeting Aβ 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.