A New Approach to Treating Alzheimer's?

Summarized by Robert W. Griffith, MD
February 12, 2004

Introduction

Pathologists looking at the brains of people dying from Alzheimer's have long known that there's an accumulation of a waxy substance, called amyloid. In fact, it's clumps or plaques of a particular 'rogue' type of amyloid, called beta-amyloid protein, or Aβ, that's been incriminated. Scientists are not sure, however, if it's the presence of Aβ itself or an effect that it produces (build-up of another rogue protein, called tau protein) that's actually responsible for the symptoms of the disease.

Whatever the precise role of Aβ in Alzheimer's, the fact that it accumulates in the disease makes it interesting to know if interference with this buildup would improve patients' symptoms. An Australian clinical trial of a drug that makes Aβ more soluble and more easily removed from the tissues has been just reported in the Archives of Neurology.

What was done

Clioquinol is an anti-infective agent that was widely used in the 1960s to prevent or treat 'traveler's diarrhea'. It was withdrawn from use in 1970 because it was linked to an unusual neurological disease - SMON¹ - in Japan. The drug is, in fact, a metal-protein-attenuating compound, which can inhibit zinc and copper from binding to Aβ, so that the Aβ can dissolve and be removed more readily.

Thirty-six patients with moderately severe Alzheimer's disease were invited to volunteer for the study. They had to have a score of 24 or less on the Mini-Mental State Examination, and a score of 20 to 45 on the appropriate part of the Alzheimer's Disease Assessment Scale (ADAS-cognitive scores). They also had to have been taking donepezil (an approved drug for treating early Alzheimer's) for 6 months; this drug was continued during the study.

The study lasted 36 weeks. The patients were given either a placebo (a sugar pill) or clioquinol in doses that were increased every 12 weeks. Blood samples were taken regularly for clioquinol, zinc, copper, and Aβ levels. The ADFAS-cog test was done at weeks 4, 12, 24, and 36.

What was found

Of the 36 subjects entering the trial, 32 provided enough information for full analysis. There were 18 treated with clioquinol, and 18 received the placebo. Several patients dropped out of the study due to unrelated incidents, so that there were 15 clioquinol and 16 patients in the final analysis.

The scientists expected that, if clioquinol worked, it would improve some mental tests results, and reduce Aβ levels in the blood and other tissues.

The first requirement was partially met: those patients who had an ADAS-cog score above 25 at baseline showed a significant slowing of their mental deterioration, compared with that in the placebo patients, at week 24, though this was less pronounced by week 36. There was no such improvement in the patients with baseline scores of 25 or below, i.e. in those who were less severely affected by the disease.

The plasma Aβ levels decreased significantly from baseline in the clioquinol-treated group from week 20 onwards; during the same period, the Aβ levels in the placebo group patients increased. In this measurement, the changes were only seen in the less severely affected patients, i.e. those with a baseline ADAS-cog below 25.

Giving clioquinol had an effect on plasma zinc levels - they were increased - but there was no effect on copper levels.

Only one serious drug-related side effect was reported. A woman had blurred vision and loss of color vision at the highest dose of clioquinol, but these symptoms disappeared on stopping the drug.

Comment

In this preliminary study, clioquinol was shown to be effective in slowing mental deterioration in patients with severe Alzheimer's, which was linked to an increase in plasma zinc levels. An accompanying editorial regards this approach to treatment as meriting 'a closer and more comprehensive assessment in larger clinical trials'.²

Slowly but surely increasing knowledge of the causes of Alzheimer's disease is yielding points of attack for new medicines. This is an example of progress in this direction, using an old, discarded drug. We await confirmation (or rejection) in future studies.

Source

• Metal-protein attenuation with iododchlorhydroxyquin (Clioquinol) targeting Aβ amyloid deposition and toxicity in Alzheimer disease. CW. Ritchie, AL. Bush, A. MacKinnon,  et al., Arch Neurol, 2003, vol. 60, pp. 1685--1691

Footnotes
1. SMON stands for systemic myelo-optic neuropathy, in which there is damage to the muscles and the eye (blindness). Clioquinol was intended to be used as an 'intestinal disinfectant'. It was prescribed in the mistaken belief that it would not to be absorbed into the body, but remain in the intestines.
2. Metal chelation therapy for Alzheimer disease. RN. Rosenberg, Editorial. Arch Neurol, 2003, vol. 60, pp. 1678--1679

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