{
  "abstract": "Chronic psychological stress has been implicated as a risk factor for Alzheimer’s disease (AD), potentially through cortisol-mediated acceleration of disease progression. However, the molecular pathways underlying this relationship remain poorly understood. Epigenetic regulation of the glucocorticoid and mineralocorticoid receptor genes (NR3C1 and NR3C2), which encode receptors for cortisol, may play an important role, but has not been examined in relation to AD progression. Therefore, this study investigated associations between DNA methylation of NR3C1/NR3C2 and AD-related phenotypes, including cognition, brain amyloid-β (Aβ) burden, and regional brain volumes. These associations were examined in two independent cohorts of cognitively unimpaired individuals with accumulating brain Aβ (n = 89–298 across outcomes) using linear regression and meta-analyses. The study also explored whether DNA methylation within NR3C1 and NR3C2 interacted with depression symptoms to influence relationships with AD-related phenotypes. While only nominal associations were observed in direct analyses, stronger associations emerged in interaction with depressive symptoms. Interaction analyses showed that relationships between DNA methylation and AD-related phenotypes (cognition, hippocampal volume and ventricular expansion) differed depending on the presence of depression symptoms. Consistent patterns across cohorts were observed, with associations primarily evident among individuals with clinically relevant depressive symptoms. One site (NR3C1 cg24052866) was associated with cognitive decline, one (NR3C1 cg08845721) with cross-sectional hippocampal volume, and eight (NR3C1 cg21979215, cg16594263; NR3C2 cg27460943, cg17253842, cg04867484, cg10993059, cg25672354, cg27234800) with ventricular expansion. These exploratory findings suggest epigenetic variation within cortisol receptor genes may influence AD-related neurodegeneration in a depression-dependent manner.",
  "abstract_shown": true,
  "affiliations": [
    "School of Diagnostic and Therapeutic Sciences, Curtin University, Kent Street, Bentley, WA 6102 Australia",
    "Curtin Medical Research Institute, Curtin University, Kent Street, Bentley, WA 6102 Australia",
    "Centre for Precision Health, Edith Cowan University, Joondalup, WA 6027 Australia",
    "Collaborative Genomics and Translation Group, School of Medical and Health Sciences, Edith Cowan University, Joondalup, WA 6027 Australia",
    "Harry Perkins Institute of Medical Research, 5 Robin Warren Dr, Murdoch, WA 6150 Australia",
    "University of Western Australia, 35 Stirling Hwy, Crawley, WA 6009 Australia",
    "Australian e-Health Research Centre, CSIRO Health and Biosecurity, Floreat, WA 6014 Australia",
    "Australian e-Health Research Centre, CSIRO Health and Biosecurity, Parkville, VIC 3052 Australia",
    "Department of Molecular Imaging & Therapy and Centre for PET, Austin Health, Heidelberg, VIC Australia",
    "Australian e-Health Research Centre, CSIRO Health and Biosecurity, Herston, QLD 4029 Australia",
    "Department of Electrical and Computer Systems Eng, Monash University, Clayton, VIC 3800 Australia",
    "Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, 3052 VIC Australia",
    "Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA USA",
    "Cogstate Ltd., Melbourne, VIC Australia",
    "School of Medical and Health Sciences, Edith Cowan University, Joondalup, WA Australia",
    "Melbourne School of Psychological Sciences, Melbourne, VIC Australia",
    "National Ageing Research Institute (NARI), Parkville, VIC Australia",
    "Australian e-Health Research Centre, CSIRO, Herston, 4029 QLD Australia",
    "Murdoch University, Murdoch, WA Australia",
    "Australian e-Health Research Centre, CSIRO, Parkville, 3052 VIC Australia",
    "University of Melbourne Academic Unit for Psychiatry of Old Age, Parkville, VIC Australia",
    "Department of Anaesthesia and Acute Pain Medicine, St Vincent’s Hospital Melbourne, Victoria Parade, Fitzroy, VIC Australia",
    "Curtin Medical School, Curtin University, Bentley, WA 6102 Australia",
    "School of Psychological Sciences and Turner Institute for Brain and Mental Health, Monash University, Melbourne, VIC Australia",
    "Department of Biomedical Sciences, Macquarie University, North Ryde, NSW Australia",
    "School of Psychological Science, University of Western Australia, Crawley, WA Australia"
  ],
  "article_type": "research article",
  "arxiv": null,
  "author_total": 79,
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  "bibtex": "https://research.draconitic.com/paper/4j131yhf54p90.bib",
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  "doi": "10.1038/s41398-026-04310-0",
  "fulltext_url": "https://pmc.ncbi.nlm.nih.gov/articles/PMC13740300/",
  "id": "4j131yhf54p90",
  "issns": [
    "2158-3188"
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  "landing_url": "https://doi.org/10.1038/s41398-026-04310-0",
  "language": "en",
  "licence": "CC-BY-NC-ND-4.0",
  "licence_label": "CC BY-NC-ND 4.0",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by-nc-nd/4.0/",
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      "2738|Dementia and Cognitive Impairment Research"
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  "pmcid": "PMC13740300",
  "pmid": "42988805",
  "published": "2026-08-10",
  "publisher": "Nature Publishing Group",
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      "origin": "openalex:2738|Dementia and Cognitive Impairment Research",
      "subfield": "psychiatry"
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  "title": "Exploring the relationship between methylation of the cortisol receptor genes and brain and cognitive outcomes in individuals with elevated amyloid-β",
  "title_text": "Exploring the relationship between methylation of the cortisol receptor genes and brain and cognitive outcomes in individuals with elevated amyloid-β",
  "type": "peer-reviewed",
  "updated_at": "2026-11-10T12:21:34Z",
  "url": "https://research.draconitic.com/paper/4j131yhf54p90",
  "venue": "Translational Psychiatry",
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