Stress and glucocorticoid exposure as a critical environmental risk factor for Alzheimer's disease

The hypothalamic-pituitary-adrenal (HPA) axis coordinates the physiological stress response by driving glucocorticoid (GC) secretion. While acute glucocorticoid signaling supports adaptive cognitive and metabolic responses, sustained activation of this system can produce hippocampal atrophy, impaired synaptic plasticity, and long-term cognitive dysfunction. Alzheimer's disease (AD), characterized by extracellular amyloid beta (Aβ) plaques and neurofibrillary tangles (NFTs), arises from interactions among genetic variants, epigenetic regulation, and environmental exposures. Here, we review clinical, epidemiological, and translational evidence implicating chronic stress and glucocorticoid exposure as a potent environmental risk factor for AD. Human observations linking stress exposure to cognitive impairment are complemented by clinical hypercortisolemia paradigms, which highlight the sensitivity of hippocampal circuits to prolonged cortisol exposure. The detrimental impact of stress on cognition is mediated by GC-responsive genes implicated in AD or, conversely, by AD genes that also respond to GCs. Animal models further support causality, showing that chronic stress or glucocorticoid exposure exacerbates Aβ accumulation, tau pathology, synaptic dysfunction, and cognition in AD-relevant systems. Finally, stress and GC exposure regulate GC or AD genes through epigenetic mechanisms, which can encode cumulative stress exposure and bias trajectories toward neurodegeneration. The involvement of stress in AD elucidates molecular mechanisms underlying its complex pathology but also provides a promising avenue of investigation for AD therapy and intervention strategies.