Introduction
Alzheimer’s Disease (AD) is a complex, aging-related neurological illness that causes steady deterioration in cognitive ability and ultimately leads to mortality (Wellen et al., 2010). In 2010, more than 30 million population was affected, and by 2050, it is expected that number will rise to 106 million worldwide. AD is known to be the seventh greatest reason for death in 2020 as well as 2021, affecting an estimated 6.5 million persons aged 65 and more (Scarmeas et al., 2009). The development of tau-mediated neurofibrillary tangles (NFTs) and the accumulation of amyloid-beta (Aβ) plaques are the primary pathophysiological marks of AD. The pathogenesis of AD is based on neuroinflammation, oxidative stress, neuronal damage, loss of synapses, and endoplasmic reticulum stress (ER) (Khan et al., 2021; Saklani et al., 2022). Inflammation triggers the cellular stress system, which further damages both cell function and the body’s metabolism in the peripheral tissues (Prabhakar et al., 2022). However, these proceedings are interconnected with Aβ oligomers and studies have shown that oligomer enhances neuronal stress by peculiarly uplifting the tumor necrosis factor α (TNF-α), eIF2α phosphorylation (eIF2α-P), reactive oxygen species (ROS), and activating JNK/PKR signaling in the models of AD (Bomfim et al., 2012; Ma et al., 2013; De Felice et al., 2014). The prefrontal cortex and the hippocampus portion of the brain exhibit these symptoms, which ultimately result in neuronal death along with the deterioration of cognitive function. However, recent research has demonstrated the involvement of metabolic dysfunction in various neuro-degenerative illnesses, like; as AD, which worsens neurological symptoms (Watson et al., 2005; Martin et al., 2009). Such metabolic dysfunctions as the uncontrolled, gradual loss of weight as well as impaired glucose tolerance are frequently seen in AD patients and have a detrimental effect on prognosis due to a poorly understood cascade of events (Cai et al., 2012). The transgenic mice with excessive Aβ expression that had decreased glucose utilization demonstrated the correlation between Aβ and metabolic dysfunction (Sharma et al., 2020). In reaction to an unbalanced metabolic equilibrium, cells undergo a well-defined physiological process called metabolic stress, which helps the cells survive. For instance, the low energy level experienced during exercise contributes to the development of harmful toxins and the advancement of metabolic stress. These toxins promote the hormonal release, the production of reactive oxygen species (ROS), hypoxia, as well as cell swelling (Wellen et al., 2010). Also, metabolic stress is allied with other diseases like obesity (Garg et al., 2021); aging (Khan et al., 2022); circadian rhythm (Ahmad., 2020); autophagy (Kalra et al., 2022); cardiomyopathy (Liu et al., 2017); inflammatory bowel disease (Schoultz et al., 2011); diabetes (Garg et al., 2022); cognitive impairment (Khan et al., 2021), etc. Numerous studies in AD suggest a connection between Aβ oligomers and disease progression. They are also thought to be neurotoxins that cause individuals to lose their memory and synapse function (Gong et al., 2003; Xia et al., 2009). In this review, we will discuss the correlation between metabolic stress and the signaling pathway FOXO in Alzheimer’s disease for a therapeutic approach.