Introduction

Thirty years ago it was found that cholinergic activity is decreased in parts of the brain (basal nuclei, ento-rhinal cortex, and hippocampus) in patients with Alzheimer disease. It was hoped that replacing this deficit would improve the symptoms of the disease, and maybe even reverse it. Two enzymes - acetyl cholinesterase and butyl cholinesterase - break down acetylcholine, and cholinesterase inhibitors can hinder their action, allowing brain choline levels to increase. Orally active forms of these, which pass the blood-brain barrier, have been developed and tested clinically. Dr Hake of the Indiana University School of Medicine has recently reviewed the clinical efficacy 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 most generally accepted scale for measuring symptoms of Alzheimer disease is the Alzheimer Disease Assessment Scale-Cognitive Subscale (ADAS-Cog), which was introduced about 15 years ago.¹ Patients are evaluated for the following items: spoken language ability, comprehension of spoken language, recall of test instructions, word-finding difficulty, following commands, naming objects, drawing, and 'ideational praxis' (each 5 points max.), orientation in time and place (8 points max.), word recall (10 points max.), and word recognition (12 points max.); giving a maximum total possible of 70 points. The higher the score, the greater the cognitive impairment. The score is expected to increase (i.e the patient will deteriorate) by 6-10 points a year in untreated Alzheimer disease patients. A 3- to 4-point improvement in score is likely to reflect clinical improvement.

Tacrine at a dose of 160 mg daily given for 30 weeks effected a mean ADAS-Cog score more than 3 points lower than patients on placebo (p<0.001). This translated into a significantly decreased likelihood of being placed in a nursing home within the following two years. While optimal responses are achieved with doses of 120 to 160 mg daily, it's best to start with a dose of 10 mg four times a day, and escalate gradually, every 4 weeks, to a maximum of 40 mg four times daily. Liver enzymes should be monitored during this period (see below).

Donepezil at a dose of 10 mg daily given for 24 weeks was associated with a greater response than placebo by nearly 3 points (p<0.05). It's suggested that dosing starts at 5 mg daily, at bedtime, for 4-6 weeks, rising to 10 mg daily. Liver function tests are not generally required.

Rivastigmine given at 6 to 12 mg daily produced a mean difference of 4 points in the ADAS-Cog scores in favor of the drug over placebo. As with other drugs of this class, the starting dose should be low - 1.5 mg twice a day increased by 3 mg daily every 2-4 weeks, to a maximum of 6 mg twice daily. Liver function testing is not mandatory.

Galantamine, unlike the other three drugs, is specific for acetylcholinesterase; moreover, it binds to nicotinic receptors, which may stimulate greater release of acetylcholine. At doses of 16 to 24 mg daily the improvement over 5 weeks was at least 3.3 points over placebo scores on the ADAS-Cog scale (p<0.001). The recommended starting dose is 4 mg twice a day for 4 weeks, and then 8 mg twice a day for another 4 weeks. The maximum dose is 12 twice daily.

Dr Hake points out that patients respond differently to this class of medication. Memory and cognition are likely to be improved, and activities of daily living can be maintained. 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, to patient and family members alike. It seems likely that starting cholinesterase inhibitors early in the disease will prevent, or delay, the deterioration that can occur if starting medication is postponed.

Adverse effects of cholinesterase inhibitors

With tacrine (as with the other drugs in this class), the most common side effects are gastrointestinal - nausea, vomiting, anorexia, and diarrhea. Hepatotoxicity occurs in a fairly high proportion of patients. Serum glutamic-pyruvic transaminase (SGPT, or ALT) should be monitored every 14 days for the first 4 months of treatment. The FDA-approved labeling gives explicit advice on the need for this monitoring, and the actions to be taken if the liver enzyme levels are increased.

Donepezil, rivastigmine and galantamine treatment is associated with significant gastrointestinal adverse reactions, including nausea and vomiting, anorexia, diarrhea, and, in the case of rivastigmine and galantamine, weight loss. Donepezil, in addition to the gastrointestinal effects, can cause muscle cramps and fatigue.

It's important to give patients the highest dose of cholinesterase inhibitors they can tolerate, to achieve the best possible results. To help with avoidance of adverse effects, the drugs can be given with food, the doses split over the course of the day, and dose escalation slowed.

Other therapeutic approaches

Epidemiological studies have suggested possible beneficial effects of a variety of medications on the development of Alzheimer disease: nicotine, estrogens, non-steroid anti-inflammatory drugs (NSAIDs), and anti-oxidants. To date, there are no results from prospective studies that support these approaches with any degree of certainty. (A prospective study of NSAIDs in preventing Alzheimer disease has given positive results).² Some pilot studies have provided data that support the use of high dose estrogen (as a patch) and a 'statin' drug with anti-inflammatory properties in treatment; links are given to these below. And, of course, intensive research into the pathogenesis of the disease is likely to yield more impressive results in the future. In the meantime, the cholinesterase inhibitors remain the best available medications available, at present.