Growing Knowledge About the Cholinergic System Shows the Evolution of Scientific Thinking

In the mid-1970s, several teams of researchers discovered that levels of a neurotransmitter called acetylcholine fell sharply in people with AD. This discovery was important because acetylcholine is critically important in the process of forming memories and is used commonly by neurons in the hippocampus and cerebral cortex–regions devastated by AD. Those early findings were reproduced and expanded upon in many studies over the following years. These studies established the fact that acetylcholine levels fall somewhat in normal aging but drop by about 90 percent in people with Alzheimer’s disease and that these steep declines are linked to memory impairment. This led to research on a broad front, including studies on the cells that use acetylcholine and the enzymes and other proteins that take part in its manufacture or activity–a framework known as the cholinergic system.

Much of this work was directed to searching for compounds that could increase the levels of acetylcholine, replace it, or slow its breakdown, all in the hopes of finding an effective treatment for AD. The two drugs that are currently approved for use in treating AD–donepezil and tacrine–act by inhibiting acetylcholinesterase, an enzyme that breaks down acetylcholine, and so maintain falling levels.

A recent study, conducted by scientists at the Mount Sinai Alzheimer’s Disease Research Center in New York, has provided an opportunity for scientists to refine their thinking about the role of the cholinergic system in the early stages of AD (Davis et al., 1999). In this study, the researchers attempted to find out whether the loss of cholinergic function in specific areas of the brain occurs before, after, or at the same time as the earliest signs of cognitive deterioration. Their findings indicate that patients in early stages of the disease, while exhibiting memory deficits and classic AD signs of plaques and tangles, have relatively normal levels of the enzymes that regulate acetylcholine levels. Only in patients with severe AD did the researchers see greatly diminished levels of these enzymes. This suggests that overall deficits of these enzymes may not be an early sign of damage in the disease. However, the researchers were not able to measure acetylcholine levels directly, so it may be possible that overall acetylcholine levels are lower, or that there is a deficit elsewhere in the cholinergic system. It is also possible that more subtle losses may still occur early on in specific neuron populations.

Given these findings, it is possible that the positive effects of the current AD drugs in patients with mild to moderate AD are due to their ability to boost normal levels of this important chemical, rather than to an ability to maintain falling levels.


National Institutes of Health

National Institute on Aging


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