Selective Muscarinic Agonists for Alzheimer Disease Treatment

Replacement therapy in Alzheimer Disease (AD) with muscarinic agonists may be of therapeutic benefit in alleviating certain cognitive deficits associated with the disorder. Based upon this “cholinergic hypothesis” (Bartus et al., 1982), a number of clinical trials were conducted over the last decade with a variety of agonists (Table I). The overall results with these compounds were equivocal with some patients reporting positive responses, some showing no responses, and others unable to complete the trials due to troublesome cholinergic side effects. Two conclusions from these studies were that either the design (e.g. outcome measures) of the trials were insufficient to determine efficacy or that the compounds themselves had major deficiencies which prevented the cholinergic hypothesis from being adequately tested.