Cholinesterase inhibition: is there evidence for disease-modifying effects?

Abstract

Background:

Cholinesterase inhibitors are broadly established as first-line symptomatic therapy for Alzheimer's disease (AD). Symptomatic effects are mediated by the inhibition of acetyl- and/or butyryl-cholinesterase (AChE and/or BuChE) – the enzymes that degrade acetylcholine (ACh) in the synapse. However, ACh is also found outside the synapse (‘extracellular ACh’) where, among other activities, it plays a role in controlling inflammation and might impact on pathological changes.

Objective/scope:

New data and clinical findings are reviewed and discussed to build a preliminary case for possible disease-modifying effects of cholinesterase inhibition.

Findings:

Trials seeking to demonstrate disease-modifying effects in subjects with mild cognitive impairment failed to reach their primary endpoints, but these failures might relate to aspects of trial methods and analyses. A re-analysis of one of these trials, using a more sensitive model controlling for factors that predict progression to AD, showed a significant delay in progression to AD with dual cholinesterase inhibition over 3 to 4 years. Taken with other evidence, it is plausible that cholinesterase inhibition might contribute to disease modification. The detection of putative disease-modifying effects may be most easily implemented in certain patient subpopulations, and genotyping studies suggest a particular role for BuChE.

Conclusion:

Long-term inhibition of BuChE might be especially important when exploring any disease-modifying effects of cholinesterase inhibitors. Elucidation of the mechanisms involved could provide insights leading to the development of new treatments that modify the development and progression of AD.

Keywords: :

• Alzheimer's disease
• Acetylcholinesterase
• Butyrylcholinesterase
• Cholinesterase inhibition
• Disease modification

Transparency

Declaration of funding

The authors take full responsibility for the views expressed in this manuscript, which may not be shared by the sponsors. The authors did not receive any remuneration for writing this manuscript. Rivastigmine and donepezil MCI trials described in this manuscript were sponsored by Novartis and Pfizer, the companies that manufacture these drugs, respectively. Novartis sponsored Alpha-Plus Medical Communications Ltd (UK) to provide editorial assistance with the production of the manuscript, under the instruction and guidance of the authors. Funding for publication support for this FastTrack article was provided by Novartis.

Declaration of funding/other relationships

M.S. is the recipient of research grants for companies manufacturing cholinesterase inhibitors; he is also a recipient of support for educational activities, and has served as a consultant on advisory boards for companies manufacturing cholinesterase inhibitors. R.B. is the recipient of research grants for companies manufacturing cholinesterase inhibitors; he is also a recipient of support for educational activities, and has served as a consultant on advisory boards for companies manufacturing cholinesterase inhibitors. M.K. is a recipient of support for educational activities, and has served as a consultant on advisory boards for companies manufacturing cholinesterase inhibitors. R.L. is an employee of, and owns stock in, Novartis.

All peer reviewers receive honoraria from CMRO for their review work. Peer Reviewer 1 and Peer Reviewer 2 have disclosed that they have no relevant financial relationships.

Acknowledgements

The authors thank Alpha-Plus Medical Communications Ltd (UK) for providing them with editorial assistance (with financial support provided by Novartis).