At least 500 million individuals are believed to suffer from diabetes mellitus (DM) throughout the world, approximately seven million individuals over the age of 18 are undiagnosed with DM, and metabolic disorders significantly impact both the central nervous system and the peripheral nervous system. Neurodegenerative disorders, such as Alzheimer’s disease. Parkinson’s disease, and Huntington’s disease, affect more than one billion individuals throughout the world, include over six hundred disorders that lead to death and disability, and current treatment protocols and lifestyle modifications for metabolic and neurodegenerative disorders cannot reverse disease burden. Innovative strategies that can robustly target both metabolic disease and neurodegenerative disorders focus on metabolic homeostasis, programmed cell death pathways, the mechanistic target of rapamycin (mTOR) and its associated pathways of mTOR Complex 1 (mTORC1), mTOR Complex 2 (mTORC2), AMP activated protein kinase (AMPK), and underlying risk factors such as the apolipoprotein E (APOE-ε4) gene. Activation of mTOR signaling can be beneficial and lead to the prevention of ß-amyloid (Aβ) toxicity, increased vascular cell survival, and enhanced neuroplasticity. However, a fine balance in activation of these pathways is necessary since in other scenarios, induction of autophagy with decreased mTOR function may result in improved memory and more robust insulin signaling that can increase Aß clearance Current investigations must address not only disease progression, but also the risk of disease onset, since the ε4 allele of the apolipoprotein E (APOE-ε4) gene has been shown to affect mTOR signaling, increase mTOR activity, and alter autophagy flux that increases risk for the development of AD and also increases the susceptibility of viral infection during coronavirus disease 2019 (COVID-19) as well as promote long-term disability with dementia and long-COVID syndrome.
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