AbstractSenile dementia of the Alzheimer type (SDAT) is a degenerative disease of the brain that affects up to 20% or more of individuals who live beyond 80 years of age. A deficiency of cholinergic function is expected to play a major role in the development of SDAT psychopathology. Possible existence of an underactive cholinergic system has led to clinical trials of cholinomimetic drugs to attempt to reverse the deficit in SDAT. Some improvement in memory function has followed the administration of cholinesterase (ChE) inhibitors, but in general the affected individuals have not been returned to normal or mildy impaired mental functions or activities of daily living functioning. This paper is a critical review of results of acute and chronic trials performed with ChE inhibitors in experimental animals and humans. We also review and discuss mechanisms of decvelopment of pharmacological behavioral tolerance to ChE inhibitors. Behavioral changes following ChE inhibition appear to coincide with predicted peak levels of acetulcholine (ACh) concentration in the brain. Yet we find an inconsistent relationship among the degree of ChE inhibition, changes in brain acetylcholine concentrations, and behavioral changes, both therapeutic and adverse effects, following administration of ChE inhibitors. ChE inhibition is associated with distressing adverse effects. The therapeutic effects of increased ACh levels in the brain may be masked by these side effects. We suggest that an adequate test of the efficacy of ChE inhibition may await the use of new and improved ChE inhibitors that produce significantly fewer side effects and greater therapeutic effects than drugs presently being tested for efficacy in the treatment of SDAT patients.