Cholinesterase inhibitors (ChEIs) were introduced in the therapy of Alzheimer Disease (AD) in the nineties with great expectations. The hopes and large interest raised by these drugs are well demonstrated by 12,000 references listed by PubMed under ChEI for 1995-2007. The list is reduced to 2500 if we confine ourselves to ChEIs and dementia. Of them about 500 were published in the last two years. Whereas an increase in brain acetylcholine and an improvement of cognitive deficits have been consistently demonstrated in animal models of AD, from aging rats to transgenic mice, ChEIs clinical effectiveness has been and is still a matter of contrasting opinions. These range from the negative conclusions of the AD2000 trial on donepezil, claiming that it is no cost effective, with benefits below minimally relevant threshold, to the NICE appraisal of 2007 declaring that donepezil, rivastigmine, galantamine are efficacious for mild to moderate AD, irrespective of their different selectivity for AChE and BuChE. The possibility that ChEIs may exert their effects through mechanisms beyond cholinesterase inhibition has been envisaged. However, according to the information presented in this review, the “classical” ChEIs, donepezil, rivastigmine and galantamine, show no pharmacological actions beyond cholinesterase inhibition which may play an important role in their therapeutic efficacy. The diverging opinions on clinical efficacy do not discourage from developing new ChEIs, and the so called multifunctional ChEIs. They represent the future of the cholinergic therapy for AD but other indications for these drugs may be considered, including vascular dementia, mild cognitive impairment, and the ethically sensitive improvement of memory and learning in healthy subjects.
An update of this review carried out four years after its first publication reveals a persistent interest for ChEIs, as demonstrated by the publication of more than 3500 preclinical and clinical papers since 2010. However, no substantial development in the field has come about, namely no novel ChEI effects have been detected beside those caused by inhibition of cholinesterases and the ensuing acetylcholine increase. The only novel indication is the extension of rivastigmine to the treatment of dementia with Lewy bodies and Parkinson’ disease dementia, in some countries.