The cholinergic hypothesis of Alzheimer's disease: a review of progress

Alzheimer's disease is one of the most common causes of mental deterioratio n in elderly people, accounting for around 50%-60% of the overall cases of dementia among persons over 65 years of age. The past two decades have witn essed a considerable research effort directed towards discovering the cause of Alzheimer's disease with the ultimate hope of developing safe and effec tive pharmacological treatments. This article examines the existing scienti fic applicability of the original cholinergic hypothesis of Alzheimer's dis ease by describing the biochemical and histopathological changes of neurotr ansmitter markers that occur in the brains of patients with Alzheimer's dis ease both at postmortem and neurosurgical cerebral biopsy and the behaviour al consequences of cholinomimetic drugs and cholinergic lesions. Such studi es have resulted in the discovery of an association between a decline in le arning and memory, and a deficit in excitatory amino acid (EAA) neurotransm ission, together with important roles for the cholinergic system in attenti onal processing and as a modulator of EAA neurotransmission. Accordingly, a lthough there is presently no "cure" for Alzheimer's disease, a large numbe r of potential therapeutic interventions have emerged that are designed to correct loss of presynaptic cholinergic function. A few of these compounds have confirmed efficacy in delaying the deterioration of symptoms of Alzhei mer's disease, a valuable treatment target considering the progressive natu re of the disease. Indeed, three compounds have received European approval for the treatment of the cognitive symptoms of Alzheimer's disease, first t acrine and more recently, donepezil and rivastigmine, all of which are chol inesterase inhibitors.