One of the early approaches for the treatment of Alzheimer disease was augmentation of cholinergic activity, based on the fact that a loss of acetylcholine occurs in the frontal cortex and the hippocampus. Physostigmine, one of the earliest cholinesterase inhibitors to be studied, produced modest improvement in cognition in some patients by inhibiting intrasynaptic degradation of acetylcholine (Drachman and Sahakian 1980). Its use was limited because of the frequent dosing required and because of severe adverse reaction. In 1993, tacrine was the first cholinesterase inhibitor to be approved for use in Alzheimer disease. The major limiting factor was its hepatotoxicity. In 1996, donepezil, a selective cholinesterase inhibitor, was approved for use in Alzheimer disease.