Stress, stress systems, and Alzheimer’s disease

AI Summary

Epidemiological evidence links chronic stress, early-life adversity and trauma to increased Alzheimer's disease risk, identifying stress as a modifiable risk factor.
Experimental models show stress hormones drive amyloid beta and tau aggregation, neuroinflammation and neurodegeneration, providing mechanistic pathways from stress to core AD pathology.
Early degeneration of stress regulatory circuits accelerates disease, decouples physiological biomarkers from perceived stress and complicates interventions and clinical trial design.

AI Summary

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. 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.

Basic summary

Alzheimers Dement. 2026 Jun;22(6):e71542. doi: 10.1002/alz.71542.

ABSTRACT

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.

PMID:42233253 | DOI:10.1002/alz.71542

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