Alzheimer's disease (AD) is a neurodegenerative disorder representing the major cause of dementia 1, 2. As per estimates, approximately 152 million individuals worldwide will live with AD by 2050 [3]. The primary clinical symptoms of AD include memory loss and cognitive dysfunction, which are linked to a synaptic loss in the brain [4]. However, the underlying biological mechanisms remain elusive, as they are influenced by factors such as aging, genetics, nutrition, and the living environment [5]. Clinical measurements [6] and the complexity of its pathogenesis also create challenges to their identification [7]. Most medications currently used in clinical settings only offer symptomatic relief and are often unable to achieve desired outcomes [8]. In the context, the potential biological mechanisms implicated in the pathogenesis of AD involve the formation of β-amyloid peptides (Aβ), development of neurofibrillary tangles (NFT) consequent to the hyperphosphorylation of tau protein, neuroinflammation, ferroptosis, oxidative stress, and disturbances of metal-ion homeostasis 4, 9, 10.

Evaluation of the complex pathological mechanisms of AD has led to an increased interest in the interactions of Aβ and tau protein with ferroptosis [11]. The accumulation of Aβ and tau protein in the brain represents one of the pathological hallmarks of AD [12] and is closely related to disruptions in iron metabolism [13]. Notably, iron is the most abundant trace element in the human body [14]. It is primarily stored in iron-containing hemosiderin to maintain the dynamic equilibrium of iron in the brain [15]. An imbalance in iron homeostasis is a crucial factor in the initiation of ferroptosis [16], a form of non-apoptotic regulatory cell death (RCD) [17]. Ferroptosis is characterized by iron-dependent accumulation of lipid peroxides and reactive oxygen species 18, 19, and is induced by disturbances in iron metabolism which acts as a catalyst for lipid peroxidation (LPO) [20]. This process compromises the integrity of the cell membrane, ultimately resulting in cell death [21]. Studies discovered that not only does the aggregation of Aβ protein promote the accumulation of iron in neuronal cells, (thereby enhancing oxidative stress) [22], but it also affects the metabolic pathways of iron (either directly or indirectly) and thereby increases ferroptosis-mediated cell death [23]. Similarly, the abnormal phosphorylation and aggregation of tau protein is related to an imbalance in iron metabolism, which intensifies the pathological effects of the tau protein and leads to further progression of AD [24]. Therefore, the study between Aβ and tau proteins with ferroptosis offers a new basis for understanding the pathology of AD and provides potential targets for developing novel therapeutic strategies.

In this review, we first describe the mechanism of ferroptosis and its close relationship with AD. We then briefly outline the currently available ferroptosis inhibitors that may improve the symptoms of AD, and finally, discuss the possible challenges to their use in the clinic. We also indicate future directions of research on the role of ferroptosis in AD. Overall, this review offers new perspectives on the treatment of AD.