Peer-reviewedCC BY-NC-ND 4.0Translational Psychiatry
Exploring the relationship between methylation of the cortisol receptor genes and brain and cognitive outcomes in individuals with elevated amyloid-β
26 affiliations
- 1School of Diagnostic and Therapeutic Sciences, Curtin University, Kent Street, Bentley, WA 6102 Australia
- 2Curtin Medical Research Institute, Curtin University, Kent Street, Bentley, WA 6102 Australia
- 3Centre for Precision Health, Edith Cowan University, Joondalup, WA 6027 Australia
- 4Collaborative Genomics and Translation Group, School of Medical and Health Sciences, Edith Cowan University, Joondalup, WA 6027 Australia
- 5Harry Perkins Institute of Medical Research, 5 Robin Warren Dr, Murdoch, WA 6150 Australia
- 6University of Western Australia, 35 Stirling Hwy, Crawley, WA 6009 Australia
- 7Australian e-Health Research Centre, CSIRO Health and Biosecurity, Floreat, WA 6014 Australia
- 8Australian e-Health Research Centre, CSIRO Health and Biosecurity, Parkville, VIC 3052 Australia
- 9Department of Molecular Imaging & Therapy and Centre for PET, Austin Health, Heidelberg, VIC Australia
- 10Australian e-Health Research Centre, CSIRO Health and Biosecurity, Herston, QLD 4029 Australia
- 11Department of Electrical and Computer Systems Eng, Monash University, Clayton, VIC 3800 Australia
- 12Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, 3052 VIC Australia
- 13Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA USA
- 14Cogstate Ltd., Melbourne, VIC Australia
- 15School of Medical and Health Sciences, Edith Cowan University, Joondalup, WA Australia
- 16Melbourne School of Psychological Sciences, Melbourne, VIC Australia
- 17National Ageing Research Institute (NARI), Parkville, VIC Australia
- 18Australian e-Health Research Centre, CSIRO, Herston, 4029 QLD Australia
- 19Murdoch University, Murdoch, WA Australia
- 20Australian e-Health Research Centre, CSIRO, Parkville, 3052 VIC Australia
- 21University of Melbourne Academic Unit for Psychiatry of Old Age, Parkville, VIC Australia
- 22Department of Anaesthesia and Acute Pain Medicine, St Vincent’s Hospital Melbourne, Victoria Parade, Fitzroy, VIC Australia
- 23Curtin Medical School, Curtin University, Bentley, WA 6102 Australia
- 24School of Psychological Sciences and Turner Institute for Brain and Mental Health, Monash University, Melbourne, VIC Australia
- 25Department of Biomedical Sciences, Macquarie University, North Ryde, NSW Australia
- 26School of Psychological Science, University of Western Australia, Crawley, WA Australia
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.
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BibTeX
@article{armstrong2026exploring,
title = {{Exploring the relationship between methylation of the cortisol receptor genes and brain and cognitive outcomes in individuals with elevated amyloid-β}},
author = {Ayeisha Milligan Armstrong and Lidija Milicic and Michael Vacher and Shane Fernandez and Eleanor K. O’Brien and Vincent Dore and Pierrick Bourgeat and Rosita Shishegar and Ying Xia and Christopher C. Rowe and Victor L. Villemagne and Paul Maruff and Colin L. Masters and Giuseppe Verdile and Simon M. Laws and David M. Groth and Tenielle Porter and Lidija Milicic and Lidija Milicic and Christopher C. Rowe and Paul Maruff and Colin L. Masters and David Ames and Sabine Bird and Julia Bomke and Pierrick Bourgeat and Belinda M. Brown and Samantha C. Burnham and Ashley I. Bush and Carolyn Chadunow and Steven Collins and James Doecke and Vincent Dore and Kathryn A. Ellis and Lis Evered and Amir Fazlollahi and Christopher Fowler and Jurgen Fripp and Samantha L. Gardener and Simon Gibson and Robert Grenfell and Elise Harrison and Richard Head and Liang Jin and Adrian Kamer and Fiona Lamb and Nicola T. Lautenschlager and Simon M. Laws and Qiao-Xin Li and Lucy Lim and Yen Ying Lim and Andrea Louey and Lucy Mackintosh and Ralph N. Martins and Simon McBride and Kelly Pertile and Tenielle Porter and Stephanie R. Rainey-Smith and Morgan Radler and Joanne Robertson},
journal = {Translational Psychiatry},
year = {2026},
month = aug,
doi = {10.1038/s41398-026-04310-0},
url = {https://doi.org/10.1038/s41398-026-04310-0},
note = {CC BY-NC-ND 4.0},
}
RIS
TY - JOUR
TI - Exploring the relationship between methylation of the cortisol receptor genes and brain and cognitive outcomes in individuals with elevated amyloid-β
AU - Ayeisha Milligan Armstrong
AU - Lidija Milicic
AU - Michael Vacher
AU - Shane Fernandez
AU - Eleanor K. O’Brien
AU - Vincent Dore
AU - Pierrick Bourgeat
AU - Rosita Shishegar
AU - Ying Xia
AU - Christopher C. Rowe
AU - Victor L. Villemagne
AU - Paul Maruff
AU - Colin L. Masters
AU - Giuseppe Verdile
AU - Simon M. Laws
AU - David M. Groth
AU - Tenielle Porter
AU - Lidija Milicic
AU - Lidija Milicic
AU - Christopher C. Rowe
AU - Paul Maruff
AU - Colin L. Masters
AU - David Ames
AU - Sabine Bird
AU - Julia Bomke
AU - Pierrick Bourgeat
AU - Belinda M. Brown
AU - Samantha C. Burnham
AU - Ashley I. Bush
AU - Carolyn Chadunow
AU - Steven Collins
AU - James Doecke
AU - Vincent Dore
AU - Kathryn A. Ellis
AU - Lis Evered
AU - Amir Fazlollahi
AU - Christopher Fowler
AU - Jurgen Fripp
AU - Samantha L. Gardener
AU - Simon Gibson
AU - Robert Grenfell
AU - Elise Harrison
AU - Richard Head
AU - Liang Jin
AU - Adrian Kamer
AU - Fiona Lamb
AU - Nicola T. Lautenschlager
AU - Simon M. Laws
AU - Qiao-Xin Li
AU - Lucy Lim
AU - Yen Ying Lim
AU - Andrea Louey
AU - Lucy Mackintosh
AU - Ralph N. Martins
AU - Simon McBride
AU - Kelly Pertile
AU - Tenielle Porter
AU - Stephanie R. Rainey-Smith
AU - Morgan Radler
AU - Joanne Robertson
PY - 2026
DA - 2026/08/10
JO - Translational Psychiatry
DO - 10.1038/s41398-026-04310-0
UR - https://doi.org/10.1038/s41398-026-04310-0
AB - 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.
SN - 2158-3188
ER -