There is substantial evidence supporting a critical role for metal ions in the
pathogenesis of Alzheimer’s disease (AD). This originated with the observation that
certain metal ions (principally copper, iron and zinc) are enriched in the neuritic
plaques of AD brains, leading to an overall reduction in their bioavailability, such
as in the synaptic cleft. Imbalances of metal ions associated with aging and AD may
affect the disease progression, leading to metals being reduced or increased from
their physiological steady state. Because metals ions are essential cofactors for many
proteins and they can compete with each other for binding to proteins, it is essential
to maintain metal homeostasis in order to preserve neuronal function. Some heavy
metals may aggravate the progression of the disease due to their high neurotoxicity
and their ability to induce epigenetic changes. On the other hand, alterations in
the levels of certain metal ions in other compartments in the brain could affect Aβ
enzymatic degradation, increase Aβ and tau aggregation as well as the processing of
the amyloid precursor protein (APP) and other intracellular processes. Metal ions are
also instrumental in enhancing the production of reactive oxygen species in the brain,
which could have consequences for neuronal viability and function. Here we review the
studies reporting the concentrations in brain, CSF and plasma in AD patients and how
alterations in their transport and storage mechanisms can lead to their redistribution in
the brain, contributing to AD neuropathology.