No response to high-dose muscarinic agonist therapy in Alzheimer's disease.

Cholinergic deficiency is the most consistent transmitter system abnormality in Alzheimer's disease. To test the acute therapeutic efficacy of cholinergic replacement, seven patients with presenile onset of Alzheimer's type dementia received maximum tolerated doses (10 mg/d) of the selective muscarinic agonist, RS-86, in combination with a peripherally active anticholinergic glycopyrrolate (6 mg/d), in a double-blind placebo-controlled design. No consistent, clinically significant cognitive improvement could be discerned in these mild to moderately demented patients, despite attainment of central RS-86 levels approximating those that affect behavior in the experimental animal. Muscarinic agonist monotherapy may thus be inadequate to benefit Alzheimer's type dementia.