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

Background: Cholinesterase inhibitors are broadly established as first-line symptomatic therapy for Alzheimer's disease (AD). Symptomatic effects are mediated by the inhibition of acetyland/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.