OBJECTIVES: The prevalence of falls in Alzheimer's disease (AD) patients is high, which leads to fractures, disability, and further worsening of cognition. Despite increased understanding of the falls in AD, the evidence on efficacious interventions addressing falls is scarce. In the absence of head-to-head trials, a network meta-analysis (NMA) was conducted to summarize the fall-related risks of pharmacological interventions used in mild-to-moderate AD patients.

METHODS: A systematic literature search was conducted in Embase, PubMed, and clinicaltrial.gov (until December-2023) to identify randomized controlled trials (RCTs) on approved and in-development interventions among mild-to-moderate AD patients (i.e., donepezil, galantamine, memantine, solanezumab, and semorinemab). Random effect Bayesian NMA was performed to calculate the odds ratio (OR) and 95% credible intervals (CrI) using R software. The node-splitting method was used to identify model inconsistencies. Surface under the cumulative ranking analysis (SUCRA) was performed to determine optimal intervention.

RESULTS: Of 2,935 hits, 12 RCTs (N=5,513, mean age=74 years, follow-up=12-52 weeks) were included following the feasibility assessment. No significant difference was observed with risk of falls between interventions vs. placebo. However, numerically lower odds (95%CrI) of falls was observed with donepezil vs. galantamine (0.53[0.16-1.7]), memantine (0.59[0.14-2.4]), and solanezumab (0.53[0.098-2.5]). Similar results were seen with semorinemab. In terms of SUCRA values, donepezil (79%) and semorinemab (71%) were more effective in reducing risk of falls than other interventions. No significant inconsistencies were observed between the direct and indirect evidence.

CONCLUSIONS: The findings suggested that though none of the interventions significantly reduced the risk of falls, these can be further evaluated as a way forward for reducing such risk potentially by targeting motor-cognitive interface. The results should be interpreted cautiously as the risks and benefits alter with disease progression and change in symptoms. Further long-term studies directly comparing the effect of these interventions on risk of falls and confirmation of their sustainability is warranted.