The recent report of positive results from a Phase IIa clinical trial of PBT2, a 
novel drug that targets amyloid-beta-metal interactions, underscores the value 
of abnormal transition metal metabolism as a potential therapeutic target in 
Alzheimer's disease. The Metals Hypothesis of Alzheimer's disease is based upon 
observations of the precipitation of amyloid-beta by zinc and its radicalization 
by copper. Both metals are markedly enriched in plaques. The Hypothesis involves 
the perturbance of these endogenous brain metals, and it does not consider 
toxicological exposure part of pathogenesis. Recent descriptions of the release 
of ionic zinc and copper in the cortical glutamatergic synapse, modulating the 
response of the NMDA receptor, may explain the vulnerability of amyloid-beta to 
abnormal interaction with these metal ions in the synaptic region leading to 
aggregation and fostering toxicity. Increasingly sophisticated medicinal 
chemistry approaches are being tested which correct the abnormalities without 
causing systemic disturbance of these essential minerals. PBT2, clioquinol and 
related compounds are ionophores rather than chelators. PBT2 is a once per day, 
orally bioavailable, second generation 8-OH quinoline derivative of clioquinol. 
It has performed very satisfactorily in toxicology and Phase I clinical trials 
and is advancing as a disease-modifying candidate drug for Alzheimer's disease.