Significance: Alzheimer's disease (AD) is the most common cause of dementia in the elderly. AD is currently ranked as the sixth leading cause of death, but some sources put it as third, after heart disease and cancer. Currently, there are no effective therapeutic approaches to treat or slow the progression of chronic neurodegeneration. In addition to the accumulation of amyloid-β (Aβ) and tau, AD patients show progressive neuronal loss and neuronal death, also high oxidative stress that correlates with abnormal levels or overload of brain metals. Recent Advances: Several promising compounds targeting oxidative stress, redox metals, and neuronal death are under preclinical or clinical evaluation as an alternative or complementary therapeutic strategy in mild cognitive impairment and AD. Here, we present a general analysis and overview, discuss limitations, and suggest potential directions for these treatments for AD and related dementia. Critical Issues: Most of the disease-modifying therapeutic strategies for AD under evaluation in clinical trials have focused on components of the amyloid cascade, including antibodies to reduce levels of Aβ and tau, as well as inhibitors of secretases. Unfortunately, several of the amyloid-focused therapeutics have failed the clinical outcomes or presented side effects, and numerous clinical trials of compounds have been halted, reducing realistic options for the development of effective AD treatments. Future Directions: The focus of research on AD and related dementias is shifting to alternative or innovative areas, such as ApoE, lipids, synapses, oxidative stress, cell death mechanisms, neuroimmunology, and neuroinflammation, as well as brain metabolism and bioenergetics.

Alzheimer’s disease (AD) is a brain disorder that progressively undermines memory and thinking skills by affecting the hippocampus and entorhinal cortex. The main histopathological hallmarks of AD are the presence of abnormal protein aggregates (Aβ and tau), synaptic dysfunction, aberrant proteostasis, cytoskeletal abnormalities, altered energy homeostasis, DNA and RNA defects, inflammation, and neuronal cell death. However, oxidative stress or oxidative damage is also evident and commonly overlooked or considered a consequence of the advancement of dementia symptoms. The control or onset of oxidative stress is linked to the activity of the amyloid-β peptide, which may serve as both antioxidant and pro-oxidant molecules. Furthermore, oxidative stress is correlated with oxidative damage to proteins, nucleic acids, and lipids in vulnerable cell populations, which ultimately lead to neuronal death through different molecular mechanisms. By recognizing oxidative stress as an integral feature of AD, alternative therapeutic or preventive interventions are developed and tested as potential or complementary therapies for this devastating neurodegenerative disease.

Abnormal accumulation of brain metals is a key feature of Alzheimer’s disease (AD). Formation of amyloid-β plaque cores (APC) is related to interactions with biometals, especially Fe, Cu and Zn, but their particular structural associations and roles remain unclear. Using an integrative set of advanced transmission electron microscopy (TEM) techniques, including spherical aberration-corrected scanning transmission electron microscopy (Cs-STEM), nano-beam electron diffraction, electron holography and analytical spectroscopy techniques (EDX and EELS), we demonstrate that Fe in APC is present as iron oxide (Fe₃O₄) magnetite nanoparticles. Here we show that Fe was accumulated primarily as nanostructured particles within APC, whereas Cu and Zn were distributed through the amyloid fibers. Remarkably, these highly organized crystalline magnetite nanostructures directly bound into fibrillar Aβ showed characteristic superparamagnetic responses with saturated magnetization with circular contours, as observed for the first time by off-axis electron holography of nanometer scale particles.

Altered metabolism of biometals in the brain is a key feature of Alzheimer's disease, and biometal interactions with amyloid-β are linked to amyloid plaque formation. Iron-rich aggregates, including evidence for the mixed-valence iron oxide magnetite, are associated with amyloid plaques. To test the hypothesis that increased chemical reduction of iron, as observed in vitro in the presence of aggregating amyloid-β, may occur at sites of amyloid plaque formation in the human brain, the nanoscale distribution and physicochemical states of biometals, particularly iron, were characterised in isolated amyloid plaque cores from human Alzheimer's disease cases using synchrotron X-ray spectromicroscopy. In situ X-ray magnetic circular dichroism revealed the presence of magnetite: a finding supported by ptychographic observation of an iron oxide crystal with the morphology of biogenic magnetite. The exceptional sensitivity and specificity of X-ray spectromicroscopy, combining chemical and magnetic probes, allowed enhanced differentiation of the iron oxides phases present. This facilitated the discovery and speciation of ferrous-rich phases and lower oxidation state phases resembling zero-valent iron as well as magnetite. Sequestered calcium was discovered in two distinct mineral forms suggesting a dynamic process of amyloid plaque calcification in vivo. The range of iron oxidation states present and the direct observation of biogenic magnetite provide unparalleled support for the hypothesis that chemical reduction of iron arises in conjunction with the formation of amyloid plaques. These new findings raise challenging questions about the relative impacts of amyloid-β aggregation, plaque formation, and disrupted metal homeostasis on the oxidative burden observed in Alzheimer's disease.