Cholinergic function and Alzheimer's disease

Abstract

Deficits in cholinergic function contribute to the pathology of Alzheimer's disease (AD), affecting cognition, behaviour and activities of daily living. Pharmacological intervention directed towards these deficits is based on acetylcholinesterase (AChE) inhibition. Whether such drugs have reached their therapeutic 'ceiling' is an open question and it is possible that cholinergic intervention may be usefully combined with other therapeutic mechanisms. Data relating to such issues are still being collected. In severe AD, levels of AChE and choline acetyltransferase are decreased by as much as 90% compared with normal, whilst butyrylcholinesterase (BuChE) increases. In such instances, it is possible that BuChE may be a more appropriate therapeutic target. Both AChE and BuChE are aggregated in senile plaques along with beta-amyloid, and investigations are being undertaken to determine whether drugs can be developed that inhibit AChE whilst also acting on beta-amyloid. Deficits in nicotinic binding sites have led to hopes for new nicotinic drugs. Cholinergic therapies can potentially cause unwanted side effects and the search for the 'ideal' inhibitor continues. Combinations of drugs may ultimately prove to be the most productive means of treating patients with AD.