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Circadian Cholinergic Rhythms: Implications for Cholinesterase Inhibitor Therapy

Therapies for Alzheimer’s disease (AD) at present augment the deteriorating cholinergic system, are reasonably well tolerated, and are convenient, given once or twice a day. They may, however, support or oppose endogenous circadian cholinergic rhythms. Drugs with a duration of action longer than a day are at odds with the physiology of the cholinergic system, which is active during the day and quiescent at night. Sleep and the consolidation of daytime experience into memory may be disturbed. Tolerance commonly develops, substantial counterregulatory increases in acetylcholinesterase (AChE) have been measured, and brain AChE inhibition is lower than predicted. Therefore, the duration of action and timing of administration, as they relate to natural cholinergic rhythms, are factors to be considered in optimizing cholinergic AD therapeutics.