Ferroptosis and its contribution to cognitive impairment in Alzheimer’s disease: mechanisms and therapeutic potential

Abstract

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder featuring cognitive impairment with loss of memory, with implications of Amyloid-β plaques and hyperphosphorylated tau tangles. Recent studies suggest that ferroptosis, an iron-dependent form of cell death characterized by the accumulation of lipid peroxides, may play a key role in the molecular and cellular pathways underlying neurodegeneration in AD. Dysregulation of iron stability is correlated to oxidative pressure and neuronal damage, especially within the hippocampus and cortex region, promoting a vicious cycle of neurodegeneration. This review focuses on summarizing major recent findings on ferroptosis towards cognitive impairment in AD involving major regulatory genes such as HIF1α and GPX4, in neuroprotection or as a risk factor of the disease. The predictive power of gene expression models based on autopsies and blood samples further highlights the importance of ferroptosis-related pathways, such as autophagy, which influences iron homeostasis and lipid degradation, and mTOR signaling, which regulates oxidative stress responses and cell survival, in shaping AD pathology and progression. Moreover, the review sheds light on novel therapeutic strategies targeting ferroptosis, such as ferroptosis inhibitors, iron chelation, and several antioxidant therapies, which hold promise for alleviating cognitive deficits and advance treatment paradigms in AD. Investigating the role of ferroptosis in AD may uncover new therapeutic strategies that target the interconnected processes of cognitive decline and neurodegeneration.