Chronic stress, cortisol dysregulation, and neurodegenerative vulnerability: mechanistic pathways linking HPA-axis dysfunction to Alzheimer's disease risk.

Chronic psychological stress is increasingly recognized as a silent risk factor of long-term brain vulnerability and a potential modifier of neurodegenerative disease trajectories. The persistent activation of the hypothalamic-pituitary-adrenal (HPA) axis and the consequent dysregulation of cortisol exert extensive influences on neural, immune, and metabolic pathways linked to cognitive decline and dementia. This review synthesizes current mechanistic and clinical evidence concerning the effects of chronic stress-induced HPA-axis dysfunction on neurodegenerative susceptibility and Alzheimer's disease risk. A structured narrative synthesis was conducted using literature from PubMed/MEDLINE, Scopus, and Web of Science, integrating multidisciplinary evidence from established biological and mechanistic domains. Present evidence suggests that prolonged exposure to glucocorticoids is associated with structural and functional alterations in the brain, including hippocampal atrophy, prefrontal cortical dysfunction, reduced synaptic plasticity, and increased amygdala activity. Chronic dysregulation of cortisol may result in neuroinflammation, disruption of the blood-brain barrier, induce mitochondrial dysfunction, and impair neuronal integrity. These interconnected mechanisms contribute to amyloid accumulation, tau pathology, and the progressive decline of neural resilience. Rather than serving as the root cause, chronic psychological stress can increase the likelihood of neurodegeneration by triggering complex interactions between the neuroendocrine and neuroimmune systems that accelerate the already existing pathological pathways toward neurodegeneration. Recognizing chronic stress as a potentially modifiable biological risk factor may improve early risk stratification and identification of HPA-axis dysregulation, ultimately driving preventive strategies targeting stress-related neurobiological pathways.