Background <p>Alzheimer disease (AD) is a progressive neurodegenerative disorder characterized by memory impairment, loss of cognitive functions and functional progression. There is some emerging evidence suggesting chronic stress is a determinant of AD onset and progression, which has not been studied critically. </p> Objective <p>This review identifies the molecular and cellular interactions between chronic stress and AD pathogenesis, with special focus given to how stress hormones, neuroinflammation, microglial activation, and the mediations of the classical AD pathological phenotypes of amyloid-beta and tau interact. </p> Methods <p>We describe processes in which the chronic stress alters brain homeostasis, plasticity and accelerates cognitive impairment by modulating hypothalamic-pituitary-adrenal (HPA) axis, causing glucocorticoid toxicity, and activating the immune response. Microglia being the prime mediators of neuroinflammation induced by stress and their role in synaptic dysfunction are given special consideration. </p> Results <p>Chronic stress promotes sustained HPA axis activation, glucocorticoid overexposure, oxidative stress, neuroinflammation, and microglial activation, all of which contribute to neuronal dysfunction and synaptic impairment. Stress-associated inflammatory cascades further accelerate amyloid-beta accumulation and tau hyperphosphorylation, thereby intensifying AD pathology and cognitive decline. </p> Conclusion <p>A unified perspective of these overlapping pathways provides a comprehensive platform on future studies, as well as discovery of new and promising therapeutic targets to alleviate stress induced pathology of AD.</p>