Clioquinol May Be Helpful in Alzheimer's Disease

Laurie Barclay, MD

December 15, 2003

Dec. 15, 2003 — The metal chelator clioquinol may reduce progression of Alzheimer's disease (AD) compared with placebo, according to the results of a pilot study published in the December issue of the Archives of Neurology.

"Plasma beta-amyloid levels declined in the clioquinol group and increased in the placebo group," write Colin L. Masters, MD, from the University of Melbourne in Parkville, Victoria, Australia, and colleagues. "The findings support a proof of concept in humans that a drug targeting metal-beta-amyloid interactions can have a significant effect on beta-amyloid metabolism, and through this, a beneficial modification on the progression of AD."

Clioquinol is a metal-protein-attenuating compound (MPAC) that inhibits zinc and copper ions from binding to beta-amyloid, thereby helping to dissolve it and prevent it from accumulating.

In this phase II clinical trial, 36 patients with moderately severe AD were randomized to receive placebo or clioquinol, 125 mg twice daily for 12 weeks, 250 mg twice daily from weeks 13 to 24, and 375 mg twice daily from weeks 25 to 36.

Cognitive testing with the Alzheimer's Disease Assessment Scale (ADAS) was performed at study entry and at weeks 4, 12, 24, and 36. Plasma levels of beta-amyloid were measured every four weeks. Compared with the placebo group, the clioquinol group had lower levels of beta-amyloid, higher levels of zinc, and better cognitive scores. ADAS scores continued to deteriorate substantially in the placebo group but declined only marginally in the clioquinol group.

Study limitations include small sample size.

"The safety profile and the biochemical efficacy of clioquinol in this population are sufficiently encouraging to allow for future trials to take this investigation of a novel therapeutic intervention (clioquinol itself or a pharmacologically improved backup) targeting beta-amyloid to the next phase," the authors write. "This class of MPAC may also be considered for related conditions such as Parkinson disease."

The National Health and Medical Research Council of Australia, the Alzheimer Association, Prana Biotechnology, and the Baxter Trust supported this study.

In an accompanying editorial, Roger N. Rosenberg, MD, from the University of Texas Southwestern Medical Center in Dallas, notes that the slowing of cognitive decline in patients treated with clioquinol was seen only in those who were more severely affected.

"Zinc-copper chelation offers promise as a new therapeutic strategy," he writes. "Clearly, it is an innovative therapeutic approach to AD and merits a closer and more comprehensive assessment in larger clinical trials."

Arch Neurol. 2003;60:1678-1679, 1685-1691

Reviewed by Gary D. Vogin, MD