Aricept™ (donepezil), Exelon™ (rivastigmine) and Reminyl™ (galantamine)

These drugs are cholinesterase inhibitors. They help preserve the ability of sick nerve endings to transmit the nerve messages to the next cell in the chain. The first of these drugs appeared in 1986, but wasn't consistently effective until ten years later when along came the new generation of cholinesterase inhibitors, and their success was rapidly recognized. How they work makes a fascinating story. Nerve messages, or impulses, travel along nerve fibres by an electrical mechanism, but the electricity is inadequate to cross the junctions between the nerve and the next cell. Nature invented a mechanism to deal with this problem: each arriving impulse releases a tiny blip of a chemical called a neurotransmitter, which diffuses very rapidly across the junction to stimulate the next cell. For Alzheimer's disease the most important neurotransmitter is acetylcholine, the one used by the nerve cells in the thinking and memory-making parts of the brain. After the acetylcholine has carried the message across the junction it's critical that it be eliminated immediately, otherwise it would keep on stimulating the downstream cell. This could be disastrous, leading to seizures for example. Nature dealt with this potential danger by ensuring that the acetylcholine is destroyed immediately after it's delivered the message, and this is done by an enzyme called cholinesterase.

Now, in Alzheimer's disease the blip of acetylcholine that is released by each arriving nerve impulse gets progressively smaller and smaller as the nerve endings get sicker and sicker, eventually becoming too small to transmit the message across the junction. Cholinesterase inhibitors prevent cholinesterase from destroying acetylcholine, and thus what little acetylcholine is released is preserved, building up to levels high enough to get the message across to the next cell. And it works! However, eventually the sick nerve endings begin to degenerate and withdraw from the junctions and messages can no longer be transferred across them. To reach this point takes usually from two to three years (but sometimes much longer), which is why cholinesterase inhibitors usually work best in the short term.

Remarkably, however, in some instances cholinesterase inhibitors seem to have been effective for as long as 8 to 10 years, and new research (including Canadian studies) is finding that donepezil can continue to have beneficial effects in improving symptoms even in advanced Alzheimer's disease. This finding fits in with other evidence that another action of cholinesterase inhibitors is somehow to protect nerve cells from damage by oxidative stress. It has to be acknowledged, though, that there is an unexplained variation among individuals as to how well they respond to cholinesterase inhibitors, and how badly they are affected by the side effects, which include diarrhea, insomnia, nausea, infection and bladder problems. To avoid side effects one drug company is trying a new method. The drug (Exelon™) is not swallowed but is contained in a skin patch from which it is absorbed directly into the body. The usual problem of patch administration is knowing the exact dosage being taken in, but this appears to have been solved, and so this approach offers substantial promise for eliminating the side effects of cholinesterase inhibitors.

The consensus remains that, though not a cure, cholinesterase inhibitors are of benefit to at least a significant proportion of those with diagnosed Alzheimer's disease, and a promising development discussed later is the use of cholinesterase inhibitors in combination with other drugs like Ebixa®.

Ebixa^® (memantine hydrochloride)

This story has to start by talking about another neurotransmitter called glutamate. Unlike acetylcholine, glutamate is not destroyed by an enzyme after doing its job of conveying the message across the junctions between nerve cells. Instead it's taken back up into the nerve endings from which it was released, or in other words, it's recycled. This uptake requires that the glutamate combines first with special receiving molecules on the nerve endings called glutamate receptors (known as NMDA receptors). However, there's a twist to the story here. All the cells of the body contain a lot of glutamate because it has important metabolic roles aside from being a neurotransmitter. When cells get sick, especially nerve cells, glutamate leaks out, and its concentrations outside the sick nerve cells can be so high that the increased amount that's taken back by way of the glutamate receptors is toxic, and indeed quite deadly. This is one of the reasons nerve cells die in Alzheimer's disease – their sickness could be initially mild, but the massive glutamate leakage and re-uptake multiplies the threat. Memantine acts by blocking the glutamate receptors and preventing the re-uptake of the glutamate into the nerve endings. The beauty of this approach is that enough glutamate gets back into the sick nerve endings to be used as a transmitter, but the massive uptake that would be toxic is prevented. Since the glutamate threat develops somewhat late in Alzheimer's disease, memantine stands as one treatment that can be effective at moderate to advanced stages of the disease. And there is better news: ongoing research is finding that combining cholinesterase inhibitors together with memantine seems to greatly improve the outcome, more than predicted from the sum of the effects of either drug alone. This combination therapy seems likely to become an exciting therapeutic approach in the future.

[The contents of this page are provided for information purposes only and do not represent advice, an endorsement or a recommendation, with respect to any product, service or enterprise, and/or the claims and properties thereof, by the Alzheimer Society of Canada. The information contained in this report was current at the time of printing, April 2008.]