Alzheimer's disease is the most common form of dementia in the elderly, and it 
is characterized by elevated brain iron levels and accumulation of copper and 
zinc in cerebral beta-amyloid deposits (e.g., senile plaques). Both ionic zinc 
and copper are able to accelerate the aggregation of Abeta, the principle 
component of beta-amyloid deposits. Copper (and iron) can also promote the 
neurotoxic redox activity of Abeta and induce oxidative cross-linking of the 
peptide into stable oligomers. Recent reports have documented the release of 
Abeta together with ionic zinc and copper in cortical glutamatergic synapses 
after excitation. This, in turn, leads to the formation of Abeta oligomers, 
which, in turn, modulates long-term potentiation by controlling synaptic levels 
of the NMDA receptor. The excessive accumulation of Abeta oligomers in the 
synaptic cleft would then be predicted to adversely affect synaptic 
neurotransmission. Based on these findings, we have proposed the "Metal 
Hypothesis of Alzheimer's Disease," which stipulates that the neuropathogenic 
effects of Abeta in Alzheimer's disease are promoted by (and possibly even 
dependent on) Abeta-metal interactions. Increasingly sophisticated 
pharmaceutical approaches are now being implemented to attenuate abnormal 
Abeta-metal interactions without causing systemic disturbance of essential 
metals. Small molecules targeting Abeta-metal interactions (e.g., PBT2) are 
currently advancing through clinical trials and show increasing promise as 
disease-modifying agents for Alzheimer's disease based on the "metal 
hypothesis."