Nicotinic treatment of Alzheimer's disease.

Approximately 20 years after the formulation of the “cholinergic hypothesis” to explain the cognitive symptoms of Alzheimer’s disease, cholinesterase therapy remains the mainstay of treatment for this disorder. Although partially effective, currently available agents have limited effects on cognitive function and long-term efficacy appears modest. Direct or indirect stimulation of nicotinic cholinergic receptors may offer an additional therapeutic strategy. Ongoing investigations of the molecular substructure of central nervous system nicotinic receptors, their accompanying pharmacology, and the effects of nicotinic agents on cognitive function have suggested the possibility that nicotinic stimulation may have beneficial effects in Alzheimer’s disease and other neuropsychiatric disorders. Studies from our laboratory and others have explored the role of central nervous system nicotinic mechanisms in normal human cognitive and behavioral functioning as well as their role in Alzheimer’s disease. Results from acute therapeutic trials with nicotine and novel nicotinic agents suggest that nicotinic stimulation in Alzheimer’s disease patients can improve the acquisition and retention of verbal and visual information and decrease errors in cognitive tasks, as well as improve accuracy and response time. Whether such results will translate into improved clinical functioning remains to be fully tested. Development of subtype-selective nicotinic agonists with an improved safety profile will enable long-term testing of the efficacy of nicotinic stimulation on cognitive performance as well as potential cytoprotective effects. Direct or indirect (allosteric) modulation of nicotinic receptor function offers a new opportunity for Alzheimer’s disease therapeutics. Biol Psychiatry 2001;49: 268–278 © 2001 Society of Biological Psychiatry