Pharmacological Overview and Future Perspectives of Cholinergic Therapy in Alzheimer's Disease

Since damage to cholinergic neurons was found widely and severely in the brain of Alzheimer's disease (AD) patients in 1970s, many clinical trials of several kinds of cholinomimetics have been actively undertaken to stimulate the central cholinergic system which might be involved in cognitive function. Although there are various drug targets to activate the cholinergic system, only cholinesterase inhibitors prevailed in the clinical trials with regard to AD. At present, three cholinesterase inhibitors donepezil, galantamine, and rivastigmine are prescribed as a symptomatic treatment for AD. This class of drugs inhibits cholinesterase which breaks down acetylcholine), thus raising the level of acetylcholine in the synaptic clefts, activating central cholinergic function and finally leading to improvement of cognitive function, as well as other symptoms associated with AD. Clinical studies revealed that cholinesterase inhibitors reliably improved clinical rating scales of the two co-primary endpoints, typical cognition measured by ADAS-cog (Alzheimer's Disease Assessment Scale cognitive subscale) and global function assessed by CIBIC-plus (Clinician's Interview-Based Impression of Change), in mild-to-moderate AD patients. Furthermore, clinical evidence has accumulated to show efficacy in other states of dementia as well, namely dementia with Lewy bodies and severe AD. In addition to their symptomatic effects in AD, recent pharmacological studies showed that some cholinesterase inhibitors displayed certain disease modifying characteristics, namely interaction with the amyloid processing pathway, neuroprotection and enhancement of adult brain neurogenesis.