Strategies that support declining cholinergic neurotransmission in Alzheimer's disease patients

With an increased public awareness of Alzheimer's disease (AD), the last two decades have witnessed an immense research effort directed towards discovering the cause of AD with the ultimate hope of developing safe and effective pharmacological treatments. Biochemical and histopathological changes of neurotransmitter markers in the brains of AD patients both at postmortem and neurosurgical cerebral biopsy have demonstrated an association between a decline in learning and memory, and a deficit in cholinergic and associated excitatory amino acid neurotransmission. These observations illustrate the selective neurotransmitter pathology of AD. Accordingly, although there is presently no 'cure' for AD, a large number of potential therapeutic strategies have emerged that are designed to correct the loss of cholinergic neurotransmission in AD. Such strategies include increasing acetylcholine synthesis, enhancing its presynaptic synthesis and/or release, potentiating its pre- or postsynaptic action, obstructing its metabolism, or by influencing the function of cholinergic neurones themselves by administration of nerve growth factor or by trans-synaptic modulation. Indeed, the cholinesterase (ChE) inhibitors have gained the most attention. Adverse events limited the usage of the first ChE inhibitors, but more recently introduced, well-tolerated compounds, for example donepezil, have confirmed efficacy in delaying the deterioration of symptoms of AD, a valuable treatment target considering the progressive nature of the disease. Other agents which affect the cholinergic system, directly or indirectly, that are in the early stages of development for the treatment of AD are also discussed.