The efficacy of donepezil combination therapy strategies in Alzheimer's disease: A systematic review and network meta-analysis

BackgroundAlzheimer's disease (AD) remains a therapeutic challenge, and adding other agents to donepezil may offer additional benefits.ObjectiveThis network meta-analysis aimed to compare the efficacy of donepezil-based combination therapies versus donepezil monotherapy in patients with AD.MethodsWe searched PubMed, Embase, Cochrane Library and Web of Science up to October 2025 for randomized-controlled trials comparing donepezil plus another drug with donepezil alone. The primary outcomes were cognitive function [Mini-Mental State Examination (MMSE), Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-cog)], behavioral function (Neuropsychiatric Inventory) and functional ability [Alzheimer's Disease Cooperative Study Activities of Daily Living (ADCS-ADL)]. A frequentist network meta-analysis was performed, and treatments were ranked by SUCRA (Surface under the cumulative ranking curve) values. Time-stratified analyses were also conducted.Results41 trials involving 9822 patients were included. Compared with placebo, several combinations significantly improved MMSE and ADAS-cog scores, with Don (Donepezil) + Mas (Masitinib) (97.5%, 92.9%), Don + NBP (DL-3-n-butylphthalide) (82.5%, 74.5%) and Don + DSC (Dengzhan shengmai capsule) (81.4%) ranking highest. For ADCS-ADL, Don + Mas (92.7%), Don + NBP (74.1%), and Don + DSC (77.1%) showed significant improvements. No combination was statistically superior to donepezil monotherapy for any outcome, but numerical trends favored combination therapy across all time windows. The certainty of evidence was mostly moderate to low.ConclusionsSeveral donepezil-based combination therapies, particularly those with masitinib, NBP, DSC, and memantine, are more effective than placebo in improving cognitive and functional outcomes in AD. Although direct comparisons with donepezil monotherapy did not reach statistical significance, consistent trends support the potential of add-on strategies. Longer-term trials are needed to confirm sustained benefits.