Dementia, including Alzheimer disease, has been found to involve a number of systems in the brain. There is evidence for a decrease in markers of cholinergic neuron activity and for changes in brain glutamate, dopamine, norepinephrine, serotonin, and somatostatin. Eventually, cholinergic neurons die or are destroyed. Treatment has focused on increasing the amount of acetylcholine in the synapse by inhibiting the breakdown of acetylcholine.
None of the drugs available for dementia alters the underlying pathology. They produce only a marginal improvement in symptoms.
Acetylcholinesterase is the enzyme the breaks down synaptically released acetylcholine (Chapter 7). Cholinesterase inhibitors have been used as nerve gases or in the treatment of myasthenia gravis. The group of cholinesterase inhibitors used in dementia appears to have a selectivity for the brain enzyme and, therefore, have fewer systemic side effects than you would predict. The cholinesterase inhibitors are used in mild-to-moderate disease.
Of the drugs currently available, tacrine is the oldest, but it has limited use. Galantamine has some additional agonist activity at nicotinic receptors to enhance release of acetylcholine.
Memantine is a noncompetitive antagonist at the NMDA subtype of glutamate receptor.
The mechanism of action of memantine in dementia is not well understood. NMDA receptors are involved in learning and memory and blocking these receptors blocks memory formation. NMDA receptors also allow calcium influx into neurons and have been implicated in excitotoxicity in the presence of excess glutamate. Memantine is a low-affinity blocker of the channel, so it is thought that memantine can block excess calcium influx but cannot block the physiological actions of glutamate involved in learning.
Memantine appears to be effective in patients on cholinesterase inhibitors.