Journal article
Exploring the relationship between methylation of the cortisol receptor genes and brain and cognitive outcomes in individuals with elevated amyloid-β
Translational psychiatry
08/10/2026
DOI: 10.1038/s41398-026-04310-0
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.
Details
- Title: Subtitle
- Exploring the relationship between methylation of the cortisol receptor genes and brain and cognitive outcomes in individuals with elevated amyloid-β
- Creators
- Ayeisha Milligan ArmstrongLidija Milicic - Edith Cowan UniversityMichael Vacher - Edith Cowan UniversityShane Fernandez - Edith Cowan UniversityEleanor K. O’Brien - Edith Cowan UniversityVincent Dore - Australian e-Health Research CentrePierrick Bourgeat - Australian e-Health Research CentreRosita Shishegar - Australian e-Health Research CentreYing Xia - Australian e-Health Research CentreChristopher C. Rowe - Florey Institute of Neuroscience and Mental HealthVictor L. Villemagne - Edith Cowan UniversityPaul Maruff - Florey Institute of Neuroscience and Mental HealthColin L. Masters - Florey Institute of Neuroscience and Mental HealthGiuseppe Verdile - Edith Cowan UniversitySimon M. Laws - Edith Cowan UniversityDavid M. Groth - Curtin UniversityTenielle Porter - Edith Cowan UniversityMichael Weiner - University of California, San FranciscoPaul Aisen - University of California San DiegoRonald Petersen - Mayo Clinic in FloridaClifford R. Jack - Mayo Clinic in FloridaWilliam Jagust - Berkeley CollegeJohn Q. Trojanowki - University of PennsylvaniaArthur W. Toga - University of Southern CaliforniaLaurel Beckett - University of California, DavisRobert C. Green - Brigham and Women's HospitalAndrew J. Saykin - Indiana University BloomingtonLeslie M. Shaw - University of PennsylvaniaEnchi Liu - Janssen (United States)Tom Montine - University of WashingtonRonald G. Thomas - University of California San DiegoMichael Donohue - University of California San DiegoSarah Walter - University of California San DiegoDevon Gessert - University of California San DiegoTamie Sather - University of California San DiegoGus Jiminez - University of California San DiegoDanielle Harvey - University of California, DavisMatthew Bernstein - University of California San DiegoNick Fox - University of LondonPaul Thompson - LAC+USC Medical CenterNorbert SchuffCharles DeCArli - University of California, DavisBret Borowski - Mayo Clinic in FloridaJeff Gunter - Mayo Clinic in FloridaMatt Senjem - Mayo Clinic in FloridaPrashanthi Vemuri - Mayo Clinic in FloridaDavid Jones - Mayo Clinic in FloridaKejal Kantarci - Mayo Clinic in FloridaChad Ward - Mayo Clinic in FloridaRobert A. Koeppe - University of MichiganNorm Foster - University of UtahEric M. Reiman - Banner Alzheimer’s InstituteKewei Chen - Banner Alzheimer’s InstituteChet Mathis - University of PittsburghSusan Landau - Berkeley CollegeJohn C. Morris - Washington University in St. LouisNigel J. Cairns - Washington University in St. LouisErin Householder - University of Southern CaliforniaLisa Taylor Reinwald - Washington University in St. LouisVirginia Lee - University of PennsylvaniaMagdalena Korecka - University of PennsylvaniaMichal Figurski - University of PennsylvaniaKaren Crawford - University of Southern CaliforniaScott Neu - University of Southern CaliforniaTatiana M. Foroud - Indiana University BloomingtonSteven Potkin - University of California, IrvineLi Shen - Indiana University BloomingtonFaber Kelley - Indiana University BloomingtonSungeun Kim - Indiana University BloomingtonKwangsik Nho - Indiana University BloomingtonZaven Kachaturian - Alzheimer's AssociationRichard Frank - General Electric (United States)Peter J. Snyder - Brown UniversitySusan Molchan - National Institutes of HealthJeffrey Kaye - Oregon Health & Science UniversityJoseph Quinn - Oregon Health & Science UniversityBetty Lind - Oregon Health & Science UniversityRaina Carter - Oregon Health & Science UniversitySara Dolen - Oregon Health & Science UniversityLon S. Schneider - University of Southern CaliforniaSonia Pawluczyk - University of Southern CaliforniaMauricio Beccera - University of Southern CaliforniaLiberty Teodoro - University of Southern CaliforniaBryan M. Spann - University of Southern CaliforniaJames Brewer - University of California San DiegoHelen Vanderswag - University of California San DiegoAdam Fleisher - University of California San DiegoJudith L. Heidebrink - University of MichiganJoanne L. Lord - University of MichiganSara S. Mason - Mayo Clinic in FloridaColleen S. Albers - Mayo Clinic in FloridaDavid Knopman - Mayo Clinic in FloridaKris Johnson - Brigham and Women's HospitalRachelle S. Doody - Baylor College of MedicineJavier Villanueva Meyer - Baylor College of MedicineMunir Chowdhury - Baylor College of MedicineSusan Rountree - Baylor College of MedicineMimi Dang - Baylor College of MedicineYaakov Stern - Columbia University Irving Medical CenterLawrence S. Honig - Columbia University Irving Medical CenterKaren L. Bell - Columbia University Irving Medical CenterBeau Ances - Washington University in St. LouisMaria Carroll - Washington University in St. LouisSue Leon - Washington University in St. LouisMark A. Mintun - Washington University in St. LouisStacy Schneider - Washington University in St. LouisAngela Oliver - University of Alabama at BirminghamRandall Griffith - University of Alabama at BirminghamDavid Clark - University of Alabama at BirminghamDavid Geldmacher - University of Alabama at BirminghamJohn Brockington - University of Alabama at BirminghamErik Roberson - University of Alabama at BirminghamHillel Grossman - Icahn School of Medicine at Mount SinaiEffie Mitsis - Icahn School of Medicine at Mount SinaiLeyla deToledo-Morrell - Rush University Medical CenterRaj C. Shah - Rush University Medical CenterRanjan DuaraDaniel VaronMaria T. GreigPeggy RobertsMarilyn Albert - Johns Hopkins UniversityChiadi Onyike - Johns Hopkins UniversityDaniel D’Agostino - Johns Hopkins UniversityStephanie Kielb - Johns Hopkins UniversityJames E. Galvin - New York UniversityDana M. Pogorelec - New York UniversityBrittany Cerbone - New York UniversityChristina A. Michel - New York UniversityHenry Rusinek - New York UniversityMony J. de Leon - New York UniversityLidia Glodzik - New York UniversitySusan De Santi - New York UniversityP. Murali Doraiswamy - Duke Medical CenterJeffrey R. Petrella - Duke Medical CenterTerence Z. Wong - Duke Medical CenterSteven E. Arnold - University of PennsylvaniaJason H. Karlawish - University of PennsylvaniaDavid A. Wolk - University of PittsburghCharles D. Smith - University of KentuckyGreg Jicha - University of KentuckyPeter Hardy - University of KentuckyPartha Sinha - University of KentuckyElizabeth Oates - University of KentuckyGary Conrad - University of KentuckyOscar L. Lopez - University of PittsburghMaryAnn Oakley - University of PittsburghDonna M. Simpson - University of PittsburghAnton P. Porsteinsson - University of Rochester MedicineBonnie S. Goldstein - University of Rochester MedicineKim Martin - University of Rochester MedicineKelly M. Makino - University of Rochester MedicineM. Saleem Ismail - University of Rochester MedicineConnie Brand - University of Rochester MedicineRuth A. Mulnard - University of California, IrvineGaby Thai - University of California, IrvineCatherine Mc Adams Ortiz - University of California, IrvineKyle Womack - The University of Texas Southwestern Medical CenterDana Mathews - The University of Texas Southwestern Medical CenterMary Quiceno - The University of Texas Southwestern Medical CenterRamon Diaz Arrastia - The University of Texas Southwestern Medical CenterRichard King - The University of Texas Southwestern Medical CenterMyron Weiner - University of California, San FranciscoKristen Martin Cook - The University of Texas Southwestern Medical CenterMichael DeVous - The University of Texas Southwestern Medical CenterAllan I. Levey - Emory UniversityJames J. Lah - Emory UniversityJanet S. Cellar - Emory UniversityJeffrey M. Burns - University of Kansas Medical CenterHeather S. Anderson - University of Kansas Medical CenterRussell H. Swerdlow - University of Kansas Medical CenterLiana Apostolova - University of California, Los AngelesKathleen Tingus - University of California, Los AngelesEllen Woo - University of California, Los AngelesDaniel H. S. SilvermanPo H. Lu - University of California, Los AngelesGeorge Bartzokis - University of California, Los AngelesNeill R. Graff RadfordFrancine Parfitt - Mayo Clinic in FloridaTracy Kendall - Mayo Clinic in FloridaHeather Johnson - Mayo Clinic in FloridaMartin R. Farlow - Indiana University BloomingtonAnn Marie Hake - Indiana University BloomingtonBrandy R. Matthews - Indiana University BloomingtonScott Herring - Indiana University BloomingtonCynthia Hunt - Indiana University BloomingtonChristopher H. van Dyck - Yale UniversityRichard E. Carson - Yale UniversityMartha G. MacAvoy - Yale UniversityHoward ChertkowHoward BergmanChris HoseinSandra Black - Sunnybrook Health Science CentreBojana Stefanovic - Sunnybrook Health Science CentreCurtis Caldwell - Sunnybrook Health Science CentreGing Yuek Robin HsiungHoward FeldmanBenita MudgeMichele Assaly PastAndrew Kertesz - St Joseph's Health CentreJohn Rogers - St Joseph's Health CentreDick Trost - St Joseph's Health CentreCharles Bernick - Cleveland ClinicDonna Munic - Cleveland ClinicDiana Kerwin - Northwestern UniversityMarek Marsel Mesulam - Northwestern UniversityKristine Lipowski - Northwestern UniversityChuang Kuo Wu - Northwestern UniversityNancy Johnson - Northwestern UniversityCarl Sadowsky - Palm Beach NeurologyWalter Martinez - Palm Beach NeurologyTeresa Villena - Palm Beach NeurologyRaymond Scott Turner - Georgetown UniversityKathleen Johnson - Brigham and Women's HospitalBrigid Reynolds - Georgetown UniversityReisa A. Sperling - Brigham and Women's HospitalKeith A. Johnson - Brigham and Women's HospitalGad Marshall - Brigham and Women's HospitalMeghan Frey - Brigham and Women's HospitalJerome Yesavage - Stanford UniversityJoy L. Taylor - Stanford UniversityBarton Lane - Stanford UniversityAllyson Rosen - Stanford UniversityJared Tinklenberg - Stanford UniversityMarwan N. Sabbagh - Banner Sun Health Research InstituteChristine M. Belden - Banner Sun Health Research InstituteSandra A. Jacobson - Banner Sun Health Research InstituteSherye A. Sirrel - Banner Sun Health Research InstituteNeil KowallRonald KillianyAndrew E. BudsonAlexander NorbashPatricia Lynn JohnsonThomas O. Obisesan - Howard UniversitySaba Wolday - Howard UniversityJoanne Allard - Howard UniversityAlan Lerner - Case Western Reserve UniversityPaula Ogrocki - Case Western Reserve UniversityLeon Hudson - Case Western Reserve UniversityEvan Fletcher - University of California, DavisOwen Carmichael - University of California, DavisJohn Olichney - University of California, DavisCharles DeCarli - University of California, DavisSmita KitturMichael Borrie - Beaumont Hospital, DearbornT. Y. Lee - Beaumont Hospital, DearbornRob Bartha - Beaumont Hospital, DearbornSterling Johnson - University of Wisconsin–MadisonSanjay Asthana - University of Wisconsin–MadisonCynthia M. Carlsson - University of Wisconsin–MadisonSteven G. Potkin - University of California, IrvineAdrian Preda - University of California, IrvineDana Nguyen - University of California, IrvinePierre Tariot - Banner Alzheimer’s InstituteStephanie Reeder - Banner Alzheimer’s InstituteVernice Bates - Dent Neurologic InstituteHoracio Capote - Dent Neurologic InstituteMichelle Rainka - Dent Neurologic InstituteDouglas W. Scharre - The Ohio State UniversityMaria Kataki - The Ohio State UniversityAnahita Adeli - The Ohio State UniversityEarl A. Zimmerman - Albany Medical Center HospitalDzintra Celmins - Albany Medical Center HospitalAlice D. Brown - Albany Medical Center HospitalGodfrey D. Pearlson - Hartford HospitalKaren Blank - Hartford HospitalKaren Anderson - Hartford HospitalRobert B. Santulli - Dartmouth–Hitchcock Medical CenterTamar J. Kitzmiller - Dartmouth–Hitchcock Medical CenterEben S. Schwartz - Dartmouth–Hitchcock Medical CenterKaycee M. Sink - Wake Forest UniversityJeff D. Williamson - Wake Forest UniversityPradeep Garg - Wake Forest UniversityFranklin Watkins - Wake Forest UniversityBrian R. Ott - Rhode Island HospitalHenry Querfurth - Rhode Island HospitalGeoffrey Tremont - Rhode Island HospitalStephen Salloway - Butler HospitalPaul Malloy - Butler HospitalStephen Correia - Butler HospitalHoward J. Rosen - University of California, San FranciscoBruce L. Miller - University of California, San FranciscoJacobo Mintzer - Medical University of South CarolinaKenneth Spicer - Medical University of South CarolinaDavid Bachman - Medical University of South CarolinaElizabether Finger - St Joseph's Health CareStephen Pasternak - St Joseph's Health CareIrina Rachinsky - St Joseph's Health CareDick Drost - St Joseph's Health CareNunzio Pomara - Nathan Kline Institute for Psychiatric ResearchRaymundo Hernando - Nathan Kline Institute for Psychiatric ResearchAntero Sarrael - Nathan Kline Institute for Psychiatric ResearchSusan K. Schultz - University of IowaLaura L. Boles PontoHyungsub Shim - University of IowaKaren Elizabeth Smith - University of IowaNorman Relkin - Cornell UniversityGloria Chaing - Cornell UniversityLisa Raudin - Cornell UniversityAmanda Smith - University of South FloridaKristin Fargher - University of South FloridaBalebail Ashok Raj - University of South FloridaDavid Ames - Florey Institute of Neuroscience and Mental HealthSabine Bird - Edith Cowan UniversityJulia Bomke - Australian e-Health Research CentreBelinda M. Brown - Murdoch UniversitySamantha C. Burnham - Edith Cowan UniversityAshley I. Bush - Florey Institute of Neuroscience and Mental HealthCarolyn Chadunow - Florey Institute of Neuroscience and Mental HealthSteven Collins - Florey Institute of Neuroscience and Mental HealthJames Doecke - Edith Cowan UniversityKathryn A. Ellis - The University of MelbourneLis Evered - St Vincent's Hospital MelbourneAmir Fazlollahi - Australian e-Health Research CentreChristopher Fowler - Florey Institute of Neuroscience and Mental HealthJurgen Fripp - Australian e-Health Research CentreSamantha L. Gardener - Edith Cowan UniversitySimon Gibson - Australian e-Health Research CentreRobert Grenfell - Australian e-Health Research CentreElise Harrison - Florey Institute of Neuroscience and Mental HealthRichard Head - Australian e-Health Research CentreLiang Jin - Florey Institute of Neuroscience and Mental HealthAdrian Kamer - Florey Institute of Neuroscience and Mental HealthFiona Lamb - Austin HealthNicola T. Lautenschlager - The University of MelbourneQiao-Xin Li - Florey Institute of Neuroscience and Mental HealthLucy Lim - Edith Cowan UniversityYen Ying Lim - Florey Institute of Neuroscience and Mental HealthAndrea Louey - Florey Institute of Neuroscience and Mental HealthLucy Mackintosh - Florey Institute of Neuroscience and Mental HealthRalph N. Martins - Edith Cowan UniversitySimon McBride - Australian e-Health Research CentreKelly Pertile - Florey Institute of Neuroscience and Mental HealthStephanie R. Rainey-Smith - Edith Cowan UniversityMorgan Radler - Florey Institute of Neuroscience and Mental HealthJoanne Robertson - Florey Institute of Neuroscience and Mental HealthMark Rodrigues - Edith Cowan UniversityRebecca Rumble - Florey Institute of Neuroscience and Mental HealthOlivier Salvado - Commonwealth Scientific and Industrial Research OrganisationGreg Savage - Macquarie UniversityBrendan Silbert - St Vincent's Hospital MelbourneMagdalene Soh - Edith Cowan UniversityHamid R. Sohrabi - Murdoch UniversityKevin Taddei - Edith Cowan UniversityTania Taddei - Edith Cowan UniversityChristine Thai - Florey Institute of Neuroscience and Mental HealthBrett Trounson - Florey Institute of Neuroscience and Mental HealthRegan Tyrrell - Austin HealthShiji Varghese - Florey Institute of Neuroscience and Mental HealthMichael Weinborn - Edith Cowan UniversityMichael Woodward - Austin HospitalAlzheimer’s Disease Neuroimaging Initiative (ADNI)
- Resource Type
- Journal article
- Publication Details
- Translational psychiatry
- DOI
- 10.1038/s41398-026-04310-0
- ISSN
- 2158-3188
- eISSN
- 2158-3188
- Publisher
- Springer Nature
- Language
- English
- Electronic publication date
- 08/10/2026
- Academic Unit
- Neurology; Radiology; Psychiatry; Psychological and Brain Sciences
- Record Identifier
- 9985218625002771
Metrics
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