Exploring the relationship between methylation of the cortisol receptor genes and brain and cognitive outcomes in individuals with elevated amyloid-β
Year: 2026
Type: article
Study design: Observational Study
Abstract: Chronic stress has been implicated as a risk factor for Alzheimer’s disease (AD), although the molecular pathways linking stress with AD are poorly understood. In this study, relationships between differential methylation of the cortisol receptor genes, the glucocorticoid and mineralocorticoid receptors (NR3C1 and NR3C2, respectively) and brain-health phenotypes (cognition, brain amyloid-b (Aβ) burden and regional brain volumes) were examined in two independent cohorts of cognitively unimpaired individuals with accumulating brain Aβ. In addition, interactions between methylation and depression/anxiety symptoms were assessed. Nominal associations between methylation and brain-health phenotypes, including cognition, brain Aβ burden, and regional brain volumes, were observed across both cohorts. Further analyses of interactions between CpG x depression/anxiety symptoms identified that the relationships between methylation and brain-health outcomes differed significantly depending on the presence of depression/anxiety symptoms. Among the observed associations, lower methylation at cg24052866 (NR3C1) was associated with faster cognitive decline, whilst lower methylation at cg07275757 (NR3C2), cg10993059 (NR3C2), and cg25708981 (NR3C1) was associated with faster brain atrophy, specifically in those individuals with depressive symptoms. These results suggest that across the four CpG sites lower methylation is associated with worse outcomes in those with depression symptoms. This work has identified relationships between methylation of cortisol receptor genes and AD phenotypes, many of these moderated by depression symptoms. These findings, highlight the need for further investigation into methylation as biomarkers for stress-related risk in AD.
Source: Translational Psychiatry
Authors: Ayeisha Milligan Armstrong, Lidija Milicic, Michael Vacher, Shane Fernandez, Eleanor K. O’Brien, Vincent Dore, Pierrick Bourgeat, Rosita Shishegar, Ying Xia, Christopher C. Rowe, Victor L. Villemagne, Paul Maruff, Colin L. Masters, Giuseppe Verdile, Simon M. Laws, David M. Groth, Tenielle Porter, On behalf of the Alzheimer’s Disease Neuroimaging Initiative (ADNI), Michael Weiner, Paul Aisen, Ronald Petersen, Clifford R. Jack, William Jagust, John Q. Trojanowki, Arthur W. Toga, Laurel Beckett, Robert C. Green, Andrew J. Saykin, Leslie M. Shaw, Enchi Liu, Tom Montine, Ronald G. Thomas, Michael Donohue, Sarah Walter, Devon Gessert, Tamie Sather, Gus Jiminez, Danielle Harvey, Matthew Bernstein, Nick Fox, Paul Thompson, Norbert Schuff, Charles DeCArli, Bret Borowski, Jeff Gunter, Matt Senjem, Prashanthi Vemuri, David Jones, Kejal Kantarci, Chad Ward, Robert A. Koeppe, Norm Foster, Eric M. Reiman, Kewei Chen, Chet Mathis, Susan Landau, John C. Morris, Nigel J. Cairns, Erin Householder, Lisa Taylor Reinwald, Virginia Lee, Magdalena Korecka, Michal Figurski, Karen Crawford, Scott Neu, Tatiana M. Foroud, Steven Potkin, Li Shen, Faber Kelley, Sungeun Kim, Kwangsik Nho, Zaven Kachaturian, Richard Frank, Peter J. Snyder, Susan Molchan, Jeffrey Kaye, Joseph Quinn, Betty Lind, Raina Carter, Sara Dolen, Lon S. Schneider, Sonia Pawluczyk, Mauricio Beccera, Liberty Teodoro, Bryan M. Spann, James Brewer, Helen Vanderswag, Adam Fleisher, Judith L. Heidebrink, Joanne L. Lord, Sara S. Mason, Colleen S. Albers, David Knopman, Kris Johnson, Rachelle S. Doody, Javier Villanueva Meyer, Munir Chowdhury, Susan Rountree, Mimi Dang, Yaakov Stern, Lawrence S. Honig, Karen L. Bell, Beau Ances, Maria Carroll, Sue Leon, Erin Householder, Mark A. Mintun, Stacy Schneider, Angela Oliver, Randall Griffith, David Clark, David Geldmacher, John Brockington, Erik Roberson, Hillel Grossman, Effie Mitsis, Leyla deToledo-Morrell, Raj C. Shah, Ranjan Duara, Daniel Varon, Maria T. Greig, Peggy Roberts, Marilyn Albert, Chiadi Onyike, Daniel D’Agostino, Stephanie Kielb, James E. Galvin, Dana M. Pogorelec, Brittany Cerbone, Christina A. Michel, Henry Rusinek, Mony J. de Leon, Lidia Glodzik, Susan De Santi, P. Murali Doraiswamy, Jeffrey R. Petrella, Terence Z. Wong, Steven E. Arnold, Jason H. Karlawish, David A. Wolk, Charles D. Smith, Greg Jicha, Peter Hardy, Partha Sinha, Elizabeth Oates, Gary Conrad, Oscar L. Lopez, MaryAnn Oakley, Donna M. Simpson, Anton P. Porsteinsson, Bonnie S. Goldstein, Kim Martin, Kelly M. Makino, M. Saleem Ismail, Connie Brand, Ruth A. Mulnard, Gaby Thai, Catherine Mc Adams Ortiz, Kyle Womack, Dana Mathews, Mary Quiceno, Ramon Diaz Arrastia, Richard King, Myron Weiner, Kristen Martin Cook, Michael DeVous, Allan I. Levey, James J. Lah, Janet S. Cellar, Jeffrey M. Burns, Heather S. Anderson, Russell H. Swerdlow, Liana Apostolova, Kathleen Tingus, Ellen Woo, Daniel H. S. Silverman, Po H. Lu, George Bartzokis, Neill R. Graff Radford, Francine Parfitt, Tracy Kendall, Heather Johnson, Martin R. Farlow, Ann Marie Hake, Brandy R. Matthews, Scott Herring, Cynthia Hunt, Christopher H. van Dyck, Richard E. Carson, Martha G. MacAvoy, Howard Chertkow, Howard Bergman, Chris Hosein, Sandra Black, Bojana Stefanovic, Curtis Caldwell, Ging Yuek Robin Hsiung, Howard Feldman, Benita Mudge, Michele Assaly Past, Andrew Kertesz, John Rogers, Dick Trost, Charles Bernick, Donna Munic, Diana Kerwin, Marek Marsel Mesulam, Kristine Lipowski, Chuang Kuo Wu, Nancy Johnson, Carl Sadowsky, Walter Martinez, Teresa Villena, Raymond Scott Turner, Kathleen Johnson, Brigid Reynolds, Reisa A. Sperling, Keith A. Johnson, Gad Marshall, Meghan Frey, Jerome Yesavage, Joy L. Taylor, Barton Lane, Allyson Rosen, Jared Tinklenberg, Marwan N. Sabbagh, Christine M. Belden, Sandra A. Jacobson, Sherye A. Sirrel, Neil Kowall, Ronald Killiany, Andrew E. Budson, Alexander Norbash, Patricia Lynn Johnson, Thomas O. Obisesan, Saba Wolday, Joanne Allard, Alan Lerner, Paula Ogrocki, Leon Hudson, Evan Fletcher, Owen Carmichael, John Olichney, Charles DeCarli, Smita Kittur, Michael Borrie, T. Y. Lee, Rob Bartha, Sterling Johnson, Sanjay Asthana, Cynthia M. Carlsson, Steven G. Potkin, Adrian Preda, Dana Nguyen, Pierre Tariot, Adam Fleisher, Stephanie Reeder, Vernice Bates, Horacio Capote, Michelle Rainka, Douglas W. Scharre, Maria Kataki, Anahita Adeli, Earl A. Zimmerman, Dzintra Celmins, Alice D. Brown, Godfrey D. Pearlson, Karen Blank, Karen Anderson, Robert B. Santulli, Tamar J. Kitzmiller, Eben S. Schwartz, Kaycee M. Sink, Jeff D. Williamson, Pradeep Garg, Franklin Watkins, Brian R. Ott, Henry Querfurth, Geoffrey Tremont, Stephen Salloway, Paul Malloy, Stephen Correia, Howard J. Rosen, Bruce L. Miller, Jacobo Mintzer, Kenneth Spicer, David Bachman, Elizabether Finger, Stephen Pasternak, Irina Rachinsky, John Rogers, Andrew Kertesz, Dick Drost, Nunzio Pomara, Raymundo Hernando, Antero Sarrael, Susan K. Schultz, Laura L. Boles Ponto, Hyungsub Shim, Karen Elizabeth Smith, Norman Relkin, Gloria Chaing, Lisa Raudin, Amanda Smith, Kristin Fargher, Balebail Ashok Raj, the Australian Imaging Biomarker and Lifestyle (AIBL) Study, David Ames, Sabine Bird, Julia Bomke, Pierrick Bourgeat, Belinda M. Brown, Samantha C. Burnham, Ashley I. Bush, Carolyn Chadunow, Steven Collins, James Doecke, Vincent Dore, Kathryn A. Ellis, Lis Evered, Amir Fazlollahi, Christopher Fowler, Jurgen Fripp, Samantha L. Gardener, Simon Gibson, Robert Grenfell, Elise Harrison, Richard Head, Liang Jin, Adrian Kamer, Fiona Lamb, Nicola T. Lautenschlager, Simon M. Laws, Qiao-Xin Li, Lucy Lim, Yen Ying Lim, Andrea Louey, Lucy Mackintosh, Ralph N. Martins, Simon McBride, Kelly Pertile, Tenielle Porter, Stephanie R. Rainey-Smith, Morgan Radler, Joanne Robertson, Mark Rodrigues, Rebecca Rumble, Olivier Salvado, Greg Savage, Rosita Shishegar, Brendan Silbert, Magdalene Soh, Hamid R. Sohrabi, Kevin Taddei, Tania Taddei, Christine Thai, Brett Trounson, Regan Tyrrell, Michael Vacher, Shiji Varghese, Victor L. Villemagne, Michael Weinborn, Michael Woodward, Ying Xia
Institutions: Edith Cowan University, Commonwealth Scientific and Industrial Research Organisation, Australian e-Health Research Centre, CSIRO Health and Biosecurity, Austin Health, Monash University, The University of Melbourne, Florey Institute of Neuroscience and Mental Health, University of Pittsburgh, Curtin University, University of California, San Francisco, The University of Texas Southwestern Medical Center, University of California San Diego, Mayo Clinic, University of California, Berkeley, University of Pennsylvania, University of Southern California, University of California, Davis, Brigham and Women's Hospital, Harvard University, Indiana University Bloomington, Janssen Alzheimer Immunotherapy Research & Development (United States), University of Washington, University of London, University of California San Francisco Medical Center, University of Michigan, University of Utah, Banner Alzheimer’s Institute, Washington University in St. Louis, University of California, Irvine, Alzheimer's Association, General Electric (United States), Brown University, National Institutes of Health, National Institute on Aging, Oregon Health & Science University, Georgetown University Medical Center, Baylor College of Medicine, Columbia University Irving Medical Center, University of Alabama at Birmingham, Icahn School of Medicine at Mount Sinai, Rush University Medical Center, Johns Hopkins University, New York University, Duke Medical Center, University of Kentucky, University of Rochester Medicine, University of Rochester, Emory University, University of Kansas Medical Center, University of California, Los Angeles, Mayo Clinic in Florida, Yale University, Jewish General Hospital, McGill University, Sunnybrook Health Science Centre, University of British Columbia, St Joseph's Health Centre, Cleveland Clinic, Lou Ruvo Brain Institute, Northwestern University, Palm Beach Neurology, Premiere Research Institute, Stanford University, Banner Sun Health Research Institute, Boston University, Howard University, Case Western Reserve University, University of Wisconsin–Madison, Dent Neurologic Institute, The Ohio State University, Albany Medical College, Hartford Hospital, Dartmouth–Hitchcock Medical Center, Wake Forest University Health Sciences, Wake Forest University, Rhode Island Hospital, Butler Hospital, Medical University of South Carolina, Nathan Kline Institute for Psychiatric Research, University of Iowa, Cornell University, University of South Florida, USF Health Byrd Alzheimer's Institute, National Ageing Research Institute, Murdoch University, St Vincent's Hospital Melbourne, Macquarie University, The University of Western Australia, Data61, Austin Hospital
Language: English
Subfield: Psychiatry and Mental health
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $5,290
Funders: Alzheimer's Association, Science and Industry Endowment Fund, EU Joint Programme – Neurodegenerative Disease Research, Commonwealth Scientific and Industrial Research Organisation, Curtin University of Technology, Edith Cowan University, Dementia Collaborative Research Centres, Australia, State Government of Victoria, Dementia Centre for Research Collaboration, Medical Research Council, National Health and Medical Research Council, National Institute on Aging
OpenAlex ID: W7202125714