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Metal-protein attenuation with iodochlorhydroxyquin (clioquinol) targeting Abeta amyloid deposition and toxicity in Alzheimer disease: a pilot phase 2 clinical trial
Ritchie CW, Bush AI, Mackinnon A, Macfarlane S, Mastwyk M, MacGregor L, Kiers L, Cherny R et al.. Archives of neurology, 2003-12-01
Topic: Brain proteins, microglia and lab models
Background Alzheimer disease (AD) may be caused by the toxic accumulation of beta-amyloid (Abeta). Objective To test this theory, we developed a clinical intervention using clioquinol, a metal-protein-attenuating compound (MPAC) that inhibits zinc and copper ions from binding to Abeta, thereby promoting Abeta dissolution and diminishing its toxic properties. Methods A pilot phase 2 clinical trial in patients with moderately severe Alzheimer disease. Results Thirty-six subjects were randomized. The effect of treatment was significant in the more severely affected group (baseline cognitive subscale score of the Alzheimer's Disease Assessment Scale, >/=25), due to a substantial worsening of scores in those taking placebo compared with minimal deterioration for the clioquinol group. Plasma Abeta42 levels declined in the clioquinol group and increased in the placebo group. Plasma zinc levels rose in the clioquinol-treated group. The drug was well tolerated. Conclusion Subject to the usual caveats inherent in studies with small sample size, this pilot phase 2 study supports further investigation of this novel treatment strategy using a metal-protein-attenuating compound.
Key findings
- Results Thirty-six subjects were randomized.
- The effect of treatment was significant in the more severely affected group (baseline cognitive subscale score of the Alzheimer's Disease Assessment Scale, >/=25), due to a substantial worsening of scores in those taking placebo compared with minimal deterioration for the clioquinol group.
Why it matters
In this small pilot phase 2 trial of 36 patients with moderately severe Alzheimer disease, clioquinol treatment was associated with significantly less worsening than placebo in the more severely affected group, and plasma Abeta42 declined in the clioquinol group while rising in the placebo group. The authors state that the small sample size limits these findings and that further investigation of this metal-protein-attenuating compound is needed.
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Study details
- Study designclinical trial
- Evidence strengthHigh
How this study scored 72/100
Published in a peer-reviewed journal, and it is a randomised controlled trial. Scored zero for sample size and effect reported because the record does not state it.
| Component | Points | Why |
|---|---|---|
| Journal tier | 7 / 10 | Tier 3 — peer-reviewed journal (Archives of neurology) |
| Journal's citation record | 3 / 4 | Archives of Neurology: journal h-index 353 (OpenAlex, 2026-10-29) |
| Study design | 11 / 12 | A randomised controlled trial (from PubMed type “Randomized Controlled Trial”) |
| Strength of evidence | 5 / 5 | Rated “high” in our summary |
| Peer-review validation | 10 / 10 | Peer-reviewed. Published as an article in a named peer-reviewed journal. |
| How recent | 1 / 5 | 2003 — older than 20 years, still counted |
| Sample size | 0 / 4 | Participant count not stated — scores zero (not stated in the record — scored 0) |
| Effect reported | 0 / 3 | No effect size reported — scores zero (not stated in the record — scored 0) |
| Studied in people | 3 / 3 | Studied in people (pubmed indexes it as a clinical or observational study) |
| Randomised / blinded | 1 / 2 | Randomised (as stated in the record) |
| Times cited | 6 / 7 | Cited 991 times (OpenAlex, 2026-10-10) |
| Citations per year | 4 / 5 | 39.6 citations a year over 25 year(s) since 2003 |
| Impact for its field and year | 5 / 6 | Cited 28.5× the average for papers of its field and year (OpenAlex FWCI) |
| Cited by studies here | 3 / 6 | Cited by 18 other studies in this library |
| Still being cited | 3 / 4 | Cited 69 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | 4 / 4 | Last-listed author Colin Louis Masters: h-index 175 (OpenAlex, whole career) |
| Institution's track record | 2 / 3 | Massachusetts General Hospital: institution h-index 2,057 (OpenAlex) |
| Multi-centre collaboration | 2 / 3 | OpenAlex lists 6 institution(s) in 4 countries |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 14676042) |
| Free to read | 0 / 2 | Behind a paywall — scores zero |
| Total | 72 / 100 | — |
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Read the original
May need a subscription Unpaywall, Europe PMC and OpenAlex found no free copy of the full text (checked 10 Oct 2026), so the publisher may charge for it. The PubMed abstract is free.
Cite this study APA, Vancouver, BibTeX · download .bib or .ris
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APA 7th
Ritchie, C. W., Bush, A. I., Mackinnon, A., Macfarlane, S., Mastwyk, M., MacGregor, L., et al. (2003). Metal-protein attenuation with iodochlorhydroxyquin (clioquinol) targeting Abeta amyloid deposition and toxicity in Alzheimer disease: a pilot phase 2 clinical trial. Archives of neurology. https://doi.org/10.1001/archneur.60.12.1685
Vancouver
Ritchie CW, Bush AI, Mackinnon A, Macfarlane S, Mastwyk M, MacGregor L, et al. Metal-protein attenuation with iodochlorhydroxyquin (clioquinol) targeting Abeta amyloid deposition and toxicity in Alzheimer disease: a pilot phase 2 clinical trial. Archives of neurology. 2003. doi:10.1001/archneur.60.12.1685. PMID: 14676042.
BibTeX
@article{ritchie2003-14676042,
author = {Ritchie, C. W. and Bush, A. I. and Mackinnon, A. and Macfarlane, S. and Mastwyk, M. and MacGregor, L. and Kiers, L. and Cherny, R. and others},
title = {{Metal-protein attenuation with iodochlorhydroxyquin (clioquinol) targeting Abeta amyloid deposition and toxicity in Alzheimer disease: a pilot phase 2 clinical trial}},
journal = {Archives of neurology},
year = {2003},
doi = {10.1001/archneur.60.12.1685},
pmid = {14676042},
url = {https://doi.org/10.1001/archneur.60.12.1685}
}
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