Background: Aggregation of beta amyloid plaques (Aβ) in the brain is one of the hallmarks of Alzheimer's disease (AD). Recent studies have shown that the change in Cu hemostasis can cause and progress AD.

Materials and Methods: The literature review and recent investigations were studied. Data were analyzed and the consistent and controversial results were compared.

Results: The amyloid precursor protein (APP) has three Copper binding sites including histidine 149, 151, 147 that plays a key role in the APP stability, folding and metabolism. APP acts as a Cu chaperon and metalloprotein in the brain. When Copper binds to these histidine residues, APP structure will be stable and reduce the generation of Aβ. At low Copper status, the conversion of APP to Aβ plaques and the risk of AD can be increased. Moreover, the excessive concentration of Copper especially inorganic Copper can also interact with Aβ plaques and produce H2O2 then oxidize it and cause cross-linked Aβ. Also, Cu toxicity increases ROS in specific regions of the brain involved in AD.

Conclusion: There are some challenges among the related studies that Copper is a protective and progressive factor in AD. It seems that both Copper deficiency and toxicity are involved in AD. So, the maintenance of Copper balance is necessary for treatment.