20.2.3.2 Treatment of Alzheimer’s Disease

There are presently no good treatments for Alzheimer’s disease (AD). The most commonly used treatment is to enhance the cholinergic system. Another approach to the treatment of Alzheimer’s is to inhibit glutamate receptors.

The cholinergic system is enhanced in Alzheimer’s disease by inhibiting acetylcholinesterase, the enzyme that breaks down acetylcholine. Inhibition of acetylcholinesterase leads to increased concentrations of acetylcholine in the synapses in the brain. However, improvements with anticholinesterases in Alzheimer’s disease are marginal. Overall the anticholinesterases cause a decrease in rate of decline in subjects with Alzheimer’s disease (Figure 20.9).

Figure 20.9 Effect of anticholinesterase in AD (Copyright QUT, Sheila Doggrell)

Most of the benefit of anticholinesterase in Alzheimer’s disease is seen in mild-to-moderate disease (i.e. the early stages of Alzheimer’s disease).

To be useful in the treatment of Alzheimer’s disease, an anticholinesterase agent must cross the blood brain barrier and have a prominent effect in the central nervous system. Doneprezil is an anticholinesterase that acts predominantly in the central nervous system, but will also have effects in the peripheral nervous system. The side effects of doneprezil are due to its widespread ability to increase the levels of acetylcholine in synapses, and they include nausea, diarrhea, vomiting and insomnia.

The other approach to treating Alzheimer’s disease is to use glutamate NMDA receptor antagonists. When glutaminergic neurones breakdown, glutamate is released, and the levels of glutamate are very high leading to excessive stimulation of glutamate receptors. It has been shown that the excessive stimulation of the glutamate NMDA receptors may have a role in the pathology of Alzheimer’s disease.

The drugs initially developed as NMDA receptor antagonists had too many adverse effects to be used in the clinic. However, an old drug that had been used for others purpose, which is an antagonist at glutamate NMDA receptors is used. The old drug is memantine. Memantine is a non-competitive and relatively weak antagonist at NMDA receptors. It has been shown to slow the decline in moderate-to-severe Alzheimer’s disease. Thus, memantine is effective in a later stage of Alzheimer’s disease than doneprezil.