Results are in from the first pilot study to test the potential benefit of clioquinol in Alzheimer's disease (AD) patients, suggesting that the drug improves cognition and lowers plasma levels of Aβ42 in some patients.

Expanding on their earlier work showing that the metal chelator can reduce plaque load in mouse models of AD (see ARF related news story), Colin Masters and colleagues at The University of Melbourne, Victoria, Australia, with Ashley Bush of Massachusetts General Hospital in Charlestown, report results from a small phase 2 trial in the December 2003 Archives of Neurology.

Sponsored by the Australian biotechnology company PRANA, first author Craig Ritchie and colleagues enrolled 36 patients in the placebo-controlled, double-blind trial, which lasted for 36 weeks. The main criteria for evaluating the efficacy of the drug were the Alzheimer's Disease Assessment Scale (ADAS-cog score) and measurements of plasma Aβ42.

Ritchie found that patients on the drug had consistently lower ADAS-cog scores than did those on placebo. For example, by week 36, scores in the treated group increased an average of just under four units, whereas in the placebo group the increase was just over six units. These differences were statistically different at weeks four and 24 of the trial (P values of 0.07 and 0.08, respectively), but not at weeks 12 and 36. By analyzing subgroups of patients with mild to moderate (ADAS-cog score 25), the authors found that the trend was more pronounced in those hardest hit by the disease. By week 36 the ADAS score in the latter group had risen by an average of about 10 units in those on placebo, but by less than four units in patients on clioquinol. Again, statistical differences were only significant at weeks four and 24 (P values of 0.01 and 0.016, respectively).

The authors found that the drug lowered plasma Aβ42levels. Over the 36 weeks of the trial, levels of the peptide rose in the placebo group by about 0.75 ng/mL on average, but in the clioquinol group it fell by about 0.5 ng/mL. Curiously, this outcome between the more and less severely affected patients ran opposite to the trend seen in ADAS-cog scores. Those with severe disease saw little difference in their plasma Aβ42, but in those with mild disease, plasma Aβ42 increased in patients on placebo by over 1.0 ng/mL, but fell by almost the same amount in those taking clioquinol. In short, patients with mild disease had a lowering of plasma Aβ42 but no significant cognitive benefit, while those with severe disease appeared to have a cognitive benefit but no change in plasma Aβ42.

"The findings support a proof of concept in humans that a drug targeting metal-Aβ interactions can have a significant effect on Aβ metabolism," state the authors. They also note that the study is subject to the usual caveats associated with small scale trials. In an accompanying editorial, Roger Rosenberg, University of Texas Southwestern Medical Center, suggests that clioquinol deserves a closer and more comprehensive assessment in larger clinical trials. Ashley Bush points out that clioquinol therapy is not designed to deplete bulk metals, as a nonspecific chelator like EDTA might. Instead, he says, clioquinol targets a more specific protein-metal biochemical interaction. Bush will debate the merits of metal-protein attenuation compounds, such as clioquinol, in an upcoming ARF live discussion on January 15 at 12 noon, EST. Stay tuned for further announcements on this event.—Tom Fagan


  1. I would like to ask Dr. Bush whether there is any evidence that clioquinol may inhibit SOD1 activity?

    Lee et al.(1) find that the neuronal adaptor protein X11α reduces Aβ levels. McLoughlin et al.(2) find that X11α interacts with the copper chaperone for SOD1 to inhibit to SOD1 activation.

    Were clioquinol to inhibit SOD1, would it then enable X11α to have a more active role in Aβ reduction?

    Does the fact that thiamine inhibits SOD1 as reported by Lee et al.(3) explain the similarities in the pathology of thiamine deficiency and AD?


    . The neuronal adaptor protein X11alpha reduces Abeta levels in the brains of Alzheimer's APPswe Tg2576 transgenic mice. J Biol Chem. 2003 Nov 21;278(47):47025-9. PubMed.

    . The neuronal adaptor protein X11alpha interacts with the copper chaperone for SOD1 and regulates SOD1 activity. J Biol Chem. 2001 Mar 23;276(12):9303-7. PubMed.

    . Regulation and the role of Cu,Zn-containing superoxide dismutase in cell cycle progression of Schizosaccharomyces pombe. Biochem Biophys Res Commun. 2002 Oct 4;297(4):854-62. PubMed.

  2. This study is interesting and provocative. Having said that:

    1. the sample size is very small;

    2. the main effect on the ADAS-cog was nonsignificant;

    3. the effect in the group with more severe AD may be driven by only a few subjects
    since the group had only about eight subjects in the clioquinol and eight in the placebo group;

    4. why plasma Aβ levels rose in the placebo group is mystifying;

    5. studies of acetylcholinesterase inhibitors and memantine all used substantially larger sample sizes. However, these were funded by pharmaceutical companies, not a small biotech company such as Prana;

    6. clioquinol is not benign—one person (of 16 exposed) developed impaired color vision.

    In sum, these data warrant a larger study.

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News Citations

  1. Two Ways to Attack Amyloid: Metal Chelator and Antibody

Further Reading

Primary Papers

  1. . Metal-protein attenuation with iodochlorhydroxyquin (clioquinol) targeting Abeta amyloid deposition and toxicity in Alzheimer disease: a pilot phase 2 clinical trial. Arch Neurol. 2003 Dec;60(12):1685-91. PubMed.
  2. . Metal chelation therapy for Alzheimer disease. Arch Neurol. 2003 Dec;60(12):1678-9. PubMed.