Cholinesterase inhibition in Alzheimer's disease: is specificity the answer?

Cholinesterase inhibitors are the standard of care for Alzheimer's disease (AD). Acetylcholinesterase (AChE) catalyzes the hydrolysis of the cholinergic neurotransmitter acetylcholine. However, the related enzyme butyrylcholinesterase (BuChE) also breaks down acetylcholine and is likewise targeted by the same clinical cholinesterase inhibitors. The lack of clinical efficacy for the highly specific and potent AChE inhibitor, (-) huperzine A, is intriguing, given the known cholinergic deficit in AD. Based on the proven efficacy of inhibitors affecting both cholinesterases and the apparent failure of specific AChE inhibition, focused BuChE inhibition seems important for more effective treatment of AD. Therefore, BuChE-selective inhibitors provide promise for improved benefit.