BACKGROUND: Alzheimer's dementia (AD) may be caused by the formation of 
extracellular senile plaques comprised of beta-amyloid (Aß). In vitro and mouse 
model studies have demonstrated that metal protein attenuating compounds (MPACs) 
promote the solubilisation and clearance of Aß.
OBJECTIVES: To evaluate the efficacy of metal protein attenuating compounds 
(MPACs) for the treatment of cognitive impairment due to Alzheimer's dementia.
SEARCH METHODS: We searched ALOIS, the Cochrane Dementia and Cognitive 
Improvement Group Specialized Register, on 29 July 2010 using the terms: 
Clioquinol OR PBT1 OR PBT2 OR "metal protein" OR MPACS OR MPAC.
SELECTION CRITERIA: Randomised double-blind trials in which treatment with an 
MPAC was administered to participants with Alzheimer's dementia in a parallel 
group comparison with placebo were included.
DATA COLLECTION AND ANALYSIS: Three review authors (RM, LJ, ELS) independently 
assessed the quality of trials according to the Cochrane Handbook for Systematic 
Reviews of Interventions.The primary outcome measure of interest was cognitive 
function (as measured by psychometric tests). The secondary outcome measures of 
interest were in the following areas: quality of life, functional performance, 
effect on carer, biomarkers, safety and adverse effects, and death.
MAIN RESULTS: Two MPAC trials were identified. One trial compared clioquinol 
(PBT1) with placebo in 36 patients and 32 had sufficient data for per protocol 
analysis. There was no statistically significant difference in cognition (as 
measured on the Alzheimer's Disease Assessment Scale - Cognition (ADAS-Cog)) 
between the active treatment and placebo groups at 36 weeks. The difference in 
mean change from baseline ADAS-Cog score in the clioquinol arm compared with the 
placebo arm at weeks 24 and 36 was a difference of 7.37 (95% confidence interval 
(CI) 1.51 to 13.24) and 6.36 (95% CI -0.50 to 13.23), respectively.There was no 
significant impact on non-cognitive symptoms or clinical global impression. One 
participant in the active treatment group developed neurological symptoms 
(impaired visual acuity and colour vision) which resolved on cessation of 
treatment and were possibly attributable to the drug.In the second trial a 
successor compound, PBT2, was compared with placebo in 78 participants with mild 
Alzheimer's dementia; all were included in the intention-to-treat analysis. 
There was no significant difference in the Neuropsychological Test Battery (NTB) 
composite, memory or executive scores between placebo and PBT2 in the least 
squares mean change from baseline at week 12. However, two executive function 
component tests of the NTB showed significant improvement over placebo in the 
PBT2 250 mg group from baseline to week 12: category fluency test (2.8 words, 
95% CI 0.1 to 5.4; P = 0.041) and trail making part B (-48.0 s, 95% CI -83.0 to 
-13.0; P = 0.009). There was no significant effect on cognition on Mini-Mental 
State Examination (MMSE) or ADAS-Cog scales. PBT2 had a favourable safety 
profile.
AUTHORS' CONCLUSIONS: There is an absence of evidence as to whether clioquinol 
(PBT1) has any positive clinical benefit for patients with AD, or whether the 
drug is safe. We have some concerns about the quality of the study methodology; 
there was an imbalance in treatment and control groups after randomisation 
(participants in the active treatment group had a higher mean pre-morbid IQ) and 
the secondary analyses of results stratified by baseline dementia severity. The 
planned phase III trial of PBT1 has been abandoned and this compound has been 
withdrawn from development. The second trial of PBT2 was more rigorously 
conducted and showed that after 12 weeks this compound appeared to be safe and 
well tolerated in people with mild Alzheimer's dementia. Larger trials are now 
required to demonstrate cognitive efficacy.