Butyrylcholinesterase: a target in the cholinergic treatment of Alzheimer's disease

In the 1990s, the first drugs to be licensed specifically for the treatment of Alzheimer's disease (AD) became available. These drugs, the cholinesterase inhibitors (ChEls), have been shown in numerous studies to be safe and effective in improving, stabilizing, or slowing deterioration in AD patients across a variety of symptoms. The success of ChEls in the treatment of AD supports the validity of the cholinergic hypothesis, which states that decreased levels of acetylcholine (ACh) are associated with the deficits in learning, memory and behavior seen in AD patients. ChEls enhance and maintain ACh levels by inhibiting ACh degradation. Originally, acetylcholinesterase (ACNE) was thought to be the sole target cholinesterase, but continued research revealed an important new candidate enzyme - butyrylcholinesterase (BuChE). Growing experimental and clinical evidence suggests that both ACNE and BuChE are involved in normal brain function and in the development and symptoms of AD. The inhibition of BuChE may, therefore, offer efficacy beyond that of ACNE inhibition alone in maintaining the functions of mental processes, behaviour and independent living which deteriorate in patients with AD. This paper reviews the original rationale for developing the ChEls and provides further information on new, clinically relevant discoveries relating to the cholinergic hypothesis.