Stress-Related Mechanisms in Alzheimer's Disease Pathogenesis

Chronic stress is increasingly recognised as a modulator of Alzheimer’s disease (AD) pathogenesis, acting through intertwined neuroendocrine, inflammatory and proteostatic pathways. Activation of the hypothalamic–pituitary–adrenal (HPA) axis elevates glucocorticoid levels, which can destabilise microtubules, impair autophagy and alter synaptic function. Elevated glucocorticoids and corticotropin-releasing hormone (CRH) amplify the activity of kinases such as GSK3β and CDK5, driving tau hyperphosphorylation and oligomerisation. Concurrently, stress hormones foster amyloid-β (Aβ) generation through upregulation of β-secretase activity and promote the extracellular release and trans-neuronal spread of pathogenic tau species. Microglial activation and neuroinflammatory signalling further exacerbate protein aggregation and synaptic loss. Social and environmental stressors, including isolation or excessive novelty, modulate plaque deposition, glial responses and behavioural outcomes in animal models. Sex-specific vulnerabilities in hippocampal BACE1 expression and translational control contribute to the higher prevalence of sporadic AD in women. Together, these findings emphasise allostatic load as a critical risk factor and suggest that targeting stress-responsive pathways may delay or attenuate disease progression.

Research from Nature Portfolio

Exposure of a familial AD mouse model to enhanced cognitive stimulation unexpectedly elevated circulating corticosterone and increased hippocampal Aβ plaque accumulation, revealing a glucocorticoid-pathology feedback loop. This work demonstrates that environments presumed to be beneficial may trigger HPA-axis dysfunction in vulnerable individuals, exacerbating amyloidogenic processing and plaque formation. The study underscores the need for designing non-pharmacological interventions that minimise stress responses to avoid aggravating AD‐related pathology.

Stress-Related Mechanisms in Alzheimer's Disease Pathogenesis publication trend

The graph below shows the total number of articles in stress-related mechanisms in alzheimer's disease pathogenesis across all publications each year (not limited to Nature Index journals).

Technical terms

Allostatic load: Cumulative physiological strain resulting from chronic activation of stress response systems.

Glucocorticoids: Steroid hormones released by the adrenal cortex that regulate metabolism, immunity and stress responses.

Hypothalamic–pituitary–adrenal (HPA) axis: Endocrine network controlling the release of stress hormones including CRH and glucocorticoids.

Corticotropin-releasing hormone (CRH): Hypothalamic peptide that initiates HPA-axis activation and downstream stress responses.

Glycogen synthase kinase-3β (GSK3β): Kinase that phosphorylates tau and other substrates, implicated in neurodegenerative signalling.

Tau hyperphosphorylation: Pathological addition of phosphate groups to tau protein, leading to misfolding, aggregation and neurofibrillary tangle formation.

Amyloid-β (Aβ): Peptide fragment of amyloid precursor protein that aggregates into extracellular plaques in AD.

Microglia: Central nervous system immune cells that respond to injury and disease by releasing cytokines and phagocytosing debris.

References

1. Glucocorticoid stress hormones stimulate vesicle-free Tau secretion and spreading in the brain. Cell Death & Disease (2024).
2. The effects of social environment on AD-related pathology in hAPP-J20 mice and tau-P301L mice. Neurobiology of Disease (2023).
3. Sex- and brain region-specific acceleration of β-amyloidogenesis following behavioral stress in a mouse model of Alzheimer's disease. Molecular Brain (2010).
4. Targeting psychologic stress signaling pathways in Alzheimer’s disease. Molecular Neurodegeneration (2017).
5. Glucocorticoid-mediated ER-mitochondria contacts reduce AMPA receptor and mitochondria trafficking into cell terminus via microtubule destabilization. Cell Death & Disease (2018).
6. How stress mediators can cumulatively contribute to Alzheimer’s disease An allostatic load approach. Dementia & Neuropsychologia (2019).
7. Risk Factors for Alzheimer’s Disease: Focus on Stress. Frontiers in Pharmacology (2019).
8. Environmental novelty exacerbates stress hormones and Aβ pathology in an Alzheimer’s model. Scientific Reports (2017).