Chronic Stress, Depression, and Alzheimer's Disease: The Triangle of Oblivion

Chronic stress and high levels of the main stress hormones, and glucocorticoids (GC), are implicated in susceptibility to brain pathologies such as depression and Alzheimer's disease (AD), as they promote neural plasticity damage and glial reactivity, which can lead to dendritic/synaptic loss, reduced neurogenesis, mood deficits, and impaired cognition. Moreover, depression is implicated in the development of AD with chronic stress being a potential link between both disorders via common neurobiological underpinnings. Hereby, we summarize and discuss the clinical and preclinical evidence related to the detrimental effect of chronic stress as a precipitator of AD through the activation of pathological mechanisms leading to the accumulation of amyloid β (Aβ) and Tau protein. Given that the modern lifestyle increasingly exposes individuals to high stress loads, it is clear that understanding the mechanistic link(s) between chronic stress, depression, and AD pathogenesis may facilitate the treatment of AD and other stress-related disorders.