Stress, stress systems, and Alzheimer's disease

Stress is increasingly recognized as an important, modifiable factor for Alzheimer's disease (AD), yet its roles in initiation, progression, and outcomes remain incompletely elucidated. Epidemiologic studies link chronic stress, early-life adversity, and trauma to increased AD risk, while experimental models have uncovered mechanisms by which stress hormones directly drive core AD pathological processes, including amyloid beta and tau aggregation, neuroinflammation, and neurodegeneration. Complicating the relationship, brain structures that regulate the stress response are themselves selectively vulnerable to early degeneration in AD. As these circuits degenerate, interpreting changes in stress biomarkers becomes more challenging, with physiological measures potentially decoupling from perceived stress. Here, we review evidence connecting stress to AD pathophysiology as both a risk factor and a driver, examine how the degeneration of stress neuroendocrine systems accelerates disease progression, and discuss implications for intervention and clinical trial design.