Because galanthamine reversibly and competitively inhibits acetylcholinesterase and enhances the response of nicotinic receptors to acetylcholine, it could, theoretically, benefit patients with Alzheimer's disease. Wilcock and colleagues conducted a large international trial of two doses of galanthamine compared with placebo in patients with mild to moderate Alzheimer's disease. They also investigated whether the apolipoprotein E4 genotype influenced the effectiveness of galanthamine therapy.

Patients were recruited from 86 clinics in Europe and Canada. Inclusion criteria included a gradual cognitive decline over at least six months, a clinical condition meeting criteria for probable Alzheimer's disease, a score of 11 to 24 on the Mini-Mental State Examination and a score of at least 12 on the cognitive subscale of the Alzheimer's disease assessment scale, and a responsible caregiver who lived with the patient or visited at least five days per week. Patients with concomitant disease were included if their conditions were controlled, but patients with neurodegenerative conditions and those who had already received cholinesterase inhibitor therapy were excluded. Patients with multi-infarct dementia; active cerebrovascular, cardiovascular or other major organ disease; epilepsy; and drug or alcohol abuse were also excluded. The patient and the caregiver had to participate in the study.

More than 600 patients were randomly assigned to treatment with 24 mg or 32 mg of galanthamine daily or an identical placebo. The principal outcomes were scores on the cognitive subscale of the Alzheimer's disease assessment scale, clinician assessment and a report by the caregiver. Other outcomes included disability ratings and activities of daily living indices. The three treatment groups had comparable baseline characteristics.

After six months, patients who received galanthamine had significantly better cognitive function than placebo-treated patients. The effect was higher with the 32-mg dosage, but both dosages produced significantly better function than placebo. Significant advantages were also documented for galanthamine in clinician assessments, caregiver reports and disability ratings. Apolipoprotein E genotype did not alter the drug's efficacy. Adverse effects were reported by 77 percent of the placebo group, 83 percent of the 24-mg group and 89 percent of the 32-mg group. The most common side effects were mild to moderate and included nausea, vomiting, diarrhea, dizziness and headache. In the galanthamine groups, 18 percent of patients discontinued treatment because of adverse effects compared with 9 percent of those assigned to placebo. Most of the discontinuations occurred early in the study.

The authors conclude that galanthamine significantly improved cognitive function and slowed functional decline in patients with Alzheimer's disease, regardless of apolipoprotein E4 status. Side effects were usually mild and resolved within five to six days of initiating therapy.