One of the earliest approaches for Alzheimer disease treatment was augmentation of cholinergic activity, which was based on the fact that there was a loss of acetylcholine 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 the severe adverse reactions it caused. In 1993, tacrine was the first cholinesterase inhibitor to be approved for use in Alzheimer disease, but it was discontinued because of its hepatotoxicity. In 1996, donepezil, a selective cholinesterase inhibitor, was approved for use in Alzheimer disease. In 2000, rivastigmine, a pseudoreversible cholinesterase inhibitor, was approved by the Food and Drug Administration, having been previously approved and used in several other countries. A transdermal preparation of rivastigmine was approved by the FDA in 2007.