OBJECTIVE：To investiga te the clinical efficacy and safety of donepezil monotherapy versus donepezil combined with memoriam in the treatment of Alzheimer ’s disease （AD）. METHODS ：Totally 100 patients with moderate and severe AD who received medical care in Sichuan Academy of Medical Sciences & Sichuan Provincial People ’s Hospital （East Hospital ）from March 2018 to March 2020 were enrolled as study subjects ，and then were divided into control group and treatment group randomly. Control group was given donepezil monotherapy treatment （initial dose of 5 mg/d，before bedtime ；after 4 weeks，the dose was changed to 10 mg/d before bedtime ；the total medication time was 6 months）. Treatment group was treated with memantine（initial dose was 5 mg/d，the dose of those without adverse reactions was increased by 5 mg until 20 mg/d，for 6 months）on the basis of the control group ，with 50 patients in each group. Montreal cognitive assessment scale （MoCA）score， MMSE score ，ADL score ，treatment response rate and the occurrence of ADR were compared between 2 groups before and after treatment. RESULTS ：Compared with same group before treatment ，MoCA score ，MMSE score and ADL score of the two groups were significantly improved after treatment （P＜0.05）. After treatment ，compared with control group ，MoCA score ，MMSE score ， ADL score and total response rate in the treatment group were significantly increased （P＜0.05），while the incidence of ADR was decreased significantly （P＜0.05）. CONCLUSIONS ：Donepezil combined with memantine has better clinical efficacy than donepezil monotherapy in the treatment of moderate and severe AD ，and is helpful to improve the neurological function of AD patients，with good safety.