The penalty of stress ‐ Epichaperomes negatively reshaping the brain in neurodegenerative disorders

Adaptation to acute and chronic stress and/or persistent stressors is a subject of wide interest in central nervous system disorders. In this context, stress is an effector of change in organismal homeostasis and the response is generated when the brain perceives a potential threat. Herein, we discuss a nuanced and granular view whereby a wide variety of genotoxic and environmental stressors, including aging, genetic risk factors, environmental exposures, and age‐ and lifestyle‐related changes, act as direct insults to cellular, as opposed to organismal, homeostasis. These two concepts of how stressors impact the central nervous system are not mutually exclusive. We discuss how maladaptive stressor‐induced changes in protein connectivity through epichaperomes, disease‐associated pathologic scaffolds composed of tightly bound chaperones, co‐chaperones, and other factors, impact intracellular protein functionality altering phenotypes, that in turn disrupt and remodel brain networks ranging from intercellular to brain connectome levels. We provide an evidence‐based view on how these maladaptive changes ranging from stressor to phenotype provide unique precision medicine opportunities for diagnostic and therapeutic development, especially in the context of neurodegenerative disorders including Alzheimer's disease where treatment options are currently limited. We discuss how stressors act as direct insults to cellular homeostasis through epichaperome formation. Epichaperomes are maladaptive disease‐associated pathologic scaffolds composed of tightly bound chaperones, co‐chaperones, and other factors. They induce proteome‐wide changes in protein–protein interaction networks, and thus impact intracellular proteome functionality, altering cellular phenotypes. This disrupts and remodels brain networks ranging from intercellular to brain connectome levels. We provide an evidence‐based view on how these maladaptive changes ranging from stressor to phenotype provide unique precision medicine opportunities for diagnostic and therapeutic development, especially in the context of neurodegenerative disorders, such as Alzheimer's disease, where treatment options are currently limited.