Preventive and Therapeutic Strategies in Alzheimer's Disease: Focus on Oxidative Stress, Redox Metals, and Ferroptosis

<b><i>Significance:</i></b> 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. <b><i>Recent Advances:</i></b> 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. <b><i>Critical Issues:</i></b> 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. <b><i>Future Directions:</i></b> 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.