The objective of this study is to determine the efficacy of donepezil for treatment of Alzheimer's disease (AD) patients drawn from clinical practice. The study design is a two center randomized, placebo-controlled, double-blinded crossover study. The setting for this study is held at the Memory disorder unit at the Massachusetts General and Brigham and Women's Hospitals. The principal investigators will recruit sixty individuals (30 male/30 female, mean age 75.0 + 9.5) with probable AD and score of <20 on the information-memory-concentration subscale of the Blessed Dementia Scale. Placebo wash-in followed in randomized sequence by 1) donepezil 5 mg per day for 6 weeks with subsequent 6 week placebo wash-out, and 2) placebo treatment for 6 weeks. Change in the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog) scores from beginning to end of the two 6 week treatment periods. Among patients completing treatment and testing for both periods (n=48), ADAS-cog scores improved 2.17 + 0.98 points on donepezil relative to placebo (95% CI 0.2-4.1 points, p<0.05). Scores returned toward baseline within 3 weeks of drug wash-out. Thre was no associated change in caregiver's global impression (proportion improved 0.24 on donepezil versus 0.22 on placebo, proportion worsened 0.27 versus 0.35; p=0.34) or on specific tests of explicit memory or verbal fluency. Contrary to reports with tacrine, the presence of the apolipoprotein Ee4 allele did not predict donepezil treatment failure. The most common adverse events related to donepezil were nausea (5 patients), diarrhea (3), ad agitation (3). Serious events possibly related to drug were seizure, pancreatitis, and syncope (1 each). This independent confirmation of data from phase III trials suggests that donepezil modestly improves cognition in AD patients encountered in clinical practice.