Is anti-cholinesterase therapy of Alzheimer's disease delaying progression?
During the last decade, a systematic effort to develop a pharmacological treatment for Alzheimer's disease (AD) resulted in three drugs being registered for the first time in the US and Europe. All three compounds are cholinesterase inhibitors (ChEI). The major therapeutic effect of ChEI on AD patients is to maintain cognitive function at a stable level during a 6-month to 1-year period of treatment, as compared to placebo. Additional drug effects are to slow down cognitive deterioration and improve behavioral and daily living activity. Recent studies show that in many patients the cognitive stabilization effect can be prolonged up to 24 months. This long-lasting effect suggests a mechanism of action other than symptomatic, and directly cholinergic. In vitro and in vivo studies have consistently demonstrated a link between cholinergic activation and amyloid precursor protein (APP) metabolism. Lesions of cholinergic nuclei cause a rapid increase in cortical APP and cholinergic synaptic function; the effect of such lesions can be reversed by ChEI treatment. A reduction in cholinergic neurotransmission, experimental or pathological, leads to amyloidogenic metabolism and contributes to the development of neuropathology and cognitive dysfunction. To explain the long-term effect of ChEI, for which evidence is available on an experimental as well as clinical level, a mechanism based on beta-amyloid metabolism is postulated. The question whether cholinergic stabilization implies simply slowing down progression of disability or also involves delay of disease progression is discussed.
Giacobini
E
E
University Hospitals of Geneva, Department of Geriatrics, University of Geneva Medical School, Thonex-Geneva, Switzerland. Ezio.Giacobini@hcuge.ch
D000368:Aged; D000544:Alzheimer Disease / Q000188:drug therapy* / Q000378:metabolism / Q000523:psychology; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002800:Cholinesterase Inhibitors / Q000627:therapeutic use*; D002986:Clinical Trials as Topic; D006801:Humans; D008959:Models, Neurological
D016229:Amyloid beta-Peptides; D002800:Cholinesterase Inhibitors