A review of butyrylcholinesterase as a therapeutic target in the treatment of Alzheimer's disease.
OBJECTIVE
To examine the role of butyrylcholinesterase (BuChE) in cholinergic signaling and neurologic conditions, such as Alzheimer's disease (AD). The rationale for inhibiting cholinesterases in the management of AD, including clinical evidence supporting use of the dual acetylcholinesterase (AChE) and BuChE inhibitor rivastigmine, is discussed.


METHODS
PubMed searches were performed using butyrylcholinesterase as a keyword. English-language articles referenced in PubMed as of September 2011 were included. Study Selection and Data Synthesis: English-language articles related to BuChE considered to be of clinical relevance to physicians were included. English-language articles specifically related to AChE were not included, as the role of AChE in cholinergic signaling and the underlying pathology of AD is well documented. Reference lists of included publications were used to supplement the search.


RESULTS
AChE and BuChE play a role in cholinergic signaling; BuChE can hydrolyze acetylcholine and compensate for AChE when levels are depleted. In the AD brain, AChE levels decrease, while BuChE levels are reportedly increased or unchanged, with changes becoming more pronounced during the disease course. Furthermore, BuChE genotype may influence AD risk and rate of disease progression. Strategies that increase acetylcholine levels (eg, cholinesterase inhibitors) demonstrate symptomatic efficacy in AD. Rivastigmine has proven cognitive efficacy in clinical trials, and data suggest that its action is mediated, in part, by inhibition of BuChE. Retrospective analyses of clinical trials provide evidence that BuChE genotype may also influence treatment response.


CONCLUSIONS
AChE-selective inhibitors and a dual AChE and BuChE inhibitor demonstrate symptomatic efficacy in AD. Mounting preclinical and clinical evidence for a role of BuChE in maintaining normal cholinergic function and the pathology of AD provides a rationale for further studies investigating use of rivastigmine in AD and the influence of BuChE genotype on observed efficacy.
Alzheimer Neurobiology Center, Karolinska Institute, Stockholm, Sweden (Drs Nordberg and Darreh-Shori); Wolfson Centre for Age-Related Diseases, King's College, London, United Kingdom (Dr Ballard); Kingshill Research Centre, Victoria Hospital, Swindon, United Kingdom (Dr Bullock); and Novartis Pharmaceuticals Corporation, East Hanover, New Jersey (Dr Somogyi).
Agneta
A
Nordberg
Clive
C
Ballard
Roger
R
Bullock
Taher
T
Darreh-Shori
Monique
M
Somogyi