Introduction

Thirty years ago scientists found that the activity of a chemical in certain parts of the brain, called acetylcholine, was decreased in people with Alzheimer's disease. It made sense to see if replacing this substance would improve the symptoms of the disease. Giving acetylcholine as a medicine was not helpful, as it didn't get into the brain. However, two enzymes - substances that break down complex chemicals - are known to inactivate acetylcholine, and recently medicines that inhibit these enzymes have been introduced. Inhibiting the action of these enzymes allows acetylcholine to increase in the brain. Orally active forms of these medicines, called cholinesterase inhibitors, have been developed and tested clinically. Dr Hake of the Indiana University School of Medicine has recently reviewed the effectiveness and safety of the four cholinesterase inhibitors available in the USA today. These are: tacrine (Cognex), donepezil (Aricept), rivastigmine (Exelon), and galantamine (Reminyl).

Effectiveness of cholinesterase inhibitors

The symptoms of Alzheimer's disease are measured by a system called the Alzheimer Disease Assessment Scale-Cognitive Subscale (ADAS-Cog), which was introduced about 15 years ago. It covers the following items: spoken language, comprehension of spoken language, recall of instructions, difficulty in word-finding, following commands, naming objects, drawing, complex movements awareness of time and place, word recall, and word recognition. Scoring allows one to follow progress in the disease - good or bad. The average patient will deteriorate by between 6-10 points a year on this scale. An improvement of 3 to 4 points equals a recognizable clinical improvement in the patient.

All four of the cholinesterase inhibitors were shown to have beneficial effects on the ADAS-Cog scale. At their highest doses given for an adequate time period the following improvements in score (compared with placebo) were seen: tacrine - more than 3 points, donepezil - nearly 3 points, rivastigmine - 4 points, and galantamine - more than 3.3 points. The size of these benefits meant a clearly decreased likelihood of the subject being put in a nursing home within the following two years.

With all 4 drugs, initial dosing was low, with gradual increases - this because of unpleasant gastrointestinal side effects (see below).

Dr Hake points out that patients respond differently to this class of medicines. Memory and thinking processes are most likely to be improved, and 'activities of daily living' should be maintained for a longer period. However, there will probably be only a temporary delay in the onset of behavioral problems. Nevertheless, the benefits of delaying the inevitable decline are considerable, both for the patient and the family members. Starting medication early is obviously therefore better.

Side effects of cholinesterase inhibitors

All four drugs in this group have gastrointestinal side effects, because of the way they work. These include nausea, vomiting, loss of appetite and diarrhea. With rivastigmine and galantamine, weight loss can occur. Tacrine can be liver-toxic in some patients, and liver function tests should be done every 2 weeks for the first 16 weeks in patients given this medication. Donepezil can cause muscle cramps and fatigue.

It's important for patients to take the highest doses they can tolerate, to try to get the best possible results. To help avoid side effects, the drugs can be given with food, the dose split over the course of the day, and dose increases delayed.

Other medications

Some studies have suggested that a number of medications may prevent the development of Alzheimer's disease: nicotine (cigarette smoking), estrogens, non-steroid anti-inflammatory drugs (NSAIDs), and anti-oxidants (e.g. vitamin E). So far, there are no convincing results from comprehensive studies that show that any of these approaches improve the symptoms or course of established Alzheimer's. However, some pilot studies support the use of high-dose estrogen (as a patch) and a 'statin' drug with anti-inflammatory properties; see the links given below. And, of course, intensive research into the way the disease is caused is likely to provide drugs with more impressive results in the future. In the meantime, the cholinesterase inhibitors give the best chance of at least delaying progress of this distressing disease.