Treating Alzheimer's disease with cholinesterase inhibitors: what have we learned so far?

For almost 90 years following the original description of Alois Alzheimer’s patient and the identification of Alzheimer’s disease (AD) (Alzheimer, 1907), physicians faced the bleak prospect of observing the inexorable and relentless decline in cognition, function, and behavior with little or no opportunity for therapeutic intervention. In the last 5 years clinicians have finally been provided with a class of medications, the cholinesterase (ChE) inhibitors, which have passed the test of efficacy and safety in the symptomatic management of AD and related dementias. With the arrival of donepezil, rivastigmine, and galantamine as the second generation of ChE inhibitors, a renewed and sustained interest in the diagnosis and care of AD patients might have been anticipated. However, there remains residual therapeutic nihilism and skepticism over the utility of these treatments in some quarters of the medical community and among some paying authorities. In moving forward and addressing these concerns, we must reflect carefully on the question, “What have we learned about the ChE inhibitors so far?” The development process of ChE inhibitors inadvertently fostered some of this reserve in the community and among funding authorities. The pivotal studies and indeed regulatory approval of the ChE inhibitors were directed towards their indication and use as cognitive enhancers. A variety of well validated psychometric scales including the Alzheimer’s Disease Assessment ScaleCognitive subscale (ADAS-Cog) (Rosen, 1984) were developed for use as primary outcome measures in clinical trials. However, their use remained outside usual care and unfamiliar to practitioners trying to understand the significance of ADAS-Cog rates of decline. The trials were short , generally lasting 12-30 weeks within a disease timeline that runs for 8-10 years. This initially left clinicians without a readily available translation of treatment effects from clinical trials to their clinical practice, as well as leaving uncertainty over the longer-term