"What we've got here is failure to communicate "
(Extra points: Name that movie! Hint: It stars Paul Newman.)

As scientists realized that Alzheimer's was not just inevitable "senility," but rather a brain disease, they found one obvious change in the brain: a decrease in acetylcholine, a neurotransmitter that carries signals across synapses between neurons. Like junction boxes in a phone network, synapses allow neurons to reach out and touch one other. Absent neurotransmitters, synapses are less effective than a phone company on a walkout.

ABOVE: The cellular signs of Alzheimer's include neurofibrillary tangles, made of tau protein, and amyloid plaques. Plaques, located between neurons, are made of beta amyloid protein. Normally, beta amyloid fragments are broken down and eliminated. In Alzheimer's, they join into insoluble plaques.
Courtesy Alzheimer’s Disease Research, a program of BrightFocus Foundation

ABOVE: Here's what the culprits look like in actual brain tissue. Healthy neurons are marked in red; tangles and plaques are in blue.
Courtesy Toshi Kinoshita, Department of Pathology, University of Wisconsin Medical School.

Acetylcholine is so vital that deadly chemicals like nerve gas, organophosphate pesticides, botulism toxin and the arrow poison curare all work by interfering with it. Doctors responded logically to the news about acetylcholine reduction: Why not restore the neurotransmitter by adding chemicals that the body can convert to acetylcholine? It was a beautiful theory, but it was overwhelmed by an ugly fact: Supplements of raw materials like choline and lecithin failed to slow Alzheimer's.

A backwards approach to the same problem works rather better. Instead of trying to make more acetylcholine, three new drugs try to preserve the chemical by interfering with an enzyme that decomposes acetylcholine. The so-called "acetylcholinesterase inhibitors" indeed reduce Alzheimer's symptoms -- to some extent, and with considerable side effects.

Double blocking action
This spring rivastigmine, a third acetylcholinesterase inhibitor, was loosed on the market, and according to psychiatrist George Grossberg, it seems even more helpful than the previous two. The new drug inhibits acetylcholinesterase -- and butylcholinesterase, a related enzyme that seems to destroy more acetylcholine as Alzheimer's progresses. By blocking the activity of both enzymes, says Grossberg, more of the neurotransmitter will be left in the synapse "so it can do its thing longer."

Grossberg, who has studied rivastigmine for five years, says that while the drug's effects vary depending on the stage of illness, "There is impressive data that rivastigmine may improve and stabilize memory, cognition, intellect, behavior and activity," in individuals with moderate or severe Alzheimer's disease.

While rivastigmine caused nausea in 47 percent of patients during early studies, Grossberg says side effects are greatly reduced if the dosage is slowly increased. Some patients, he says, have been taking the drug for five years.

Are you getting it?
In the United States, the acetylcholinesterase inhibitors are the only approved treatment for Alzheimer's, and, faced with no other treatment options, you'd expect every Alzheimer's patient would be begging for one of them. Not so. Grossberg says fewer than 25 percent of patients are taking them, largely due to fear of side effects among diagnosed Alzheimer's patients -- and the many patients who don't know they are afflicted.

"I think the diagnosis is not being made early enough," says Grossberg. "Health care providers are not doing a good enough job."

Hardly the ideal solution
Another reason for the low use of cholinesterase inhibitors may be their relatively small overall benefit. By e-mail, Leon Flicker, a professor of geriatrics at the University of Western Australia, wrote that "The drugs are overall modestly effective but my clinical experience is that they do not work in everyone. Some patients get dramatic benefits. ... On average the effect on a group of patients is modest."

Nonetheless, Flicker says it's "probably worthwhile" testing the drugs on "quite a large number of patients" and that something is better than nothing. "They are the only available class of treatment where substantial evidence exists for efficacy" (see "Acetylcholine Inhibitors for Alzheimer's..." in the bibliography).

Indeed, while it's more desirable to treat root causes than symptoms, at this point Grossberg says the "Inhibitors produce symptomatic improvements in different domains, and may moderate the progression, buying people more quality, functional time. It's great, it may keep them independent, at home longer, there's less likelihood of institutionalization."

So are any good diagnostic techniques on the horizon?