The timeline of brain aging in major depression: A prospective study from before first-onset to established illness
Year: 2026
Type: preprint
Study design: Observational Study
Abstract: Major depressive disorder (MDD) has been associated with accelerated structural brain aging, yet whether this reflects a pre-existing neurobiological vulnerability, a dynamic acute state effect, or an accumulating biological residual remains unresolved. Across two longitudinal cohorts (N=3220), including a unique sample of 78 initially healthy individuals who transitioned into their first depressive episode during the study course, we systematically tested all three hypotheses. Patients with diagnosed MDD showed elevated MRI-derived brain age relative to healthy controls (1.4 and 2.5 years across cohorts). For the vulnerability hypothesis, individuals scanned prior to their first episode showed no baseline elevation, despite already demonstrating subclinical elevations in self-reported symptom severity, indicating that advanced brain age does not precede illness onset. For the state hypothesis, we found no acceleration of brain aging following the first depressive episode, and longitudinal brain age trajectories were independent of acute clinical symptom severity. Finally, neither episode duration nor recurrence scaled with brain age. Accelerated brain aging in depression is therefore neither an antecedent vulnerability nor an acute state marker of the first episode, but rather a stable biological feature of a long term illness course.
Source: medRxiv
Authors: Maximilian Konowski, Anna Kraus, Janik Goltermann, Jan Ernsting, Keyvan Mahjoory, Lukas Fisch, Jennifer Spanagel, Sarah Wellms, Dunya Bedir, Luisa Altegoer, Tiana Borgers, Sabrina Teckentrup, Sara Papenbrock, Anne Sophie Hildebrand, Elilarasi Ratnalingam, Eva Meisenzahl, Franziska Herrmann, Susanne Meinert, Elisabeth Johanna Leehr, Julia Hubbert, Judith Krieger, Hannah Meinert, Hannah Meinert, Theresa Slump, Igor Nenadic, Andreas Jansen, Nooshin Javaheripour, Florian Thomas-Odenthal, Hamidreza Jamalabadai, Benjamin Straube, Marco Hermesdorf, Maike Richter, Raimund Helbok, Xiaoyi Jiang, Nils Opel, Klaus Berger, Tilo Kircher, Udo Dannlowski, Tim Hahn, Nils Ralf Winter, Ramona Leenings
Language: English
Subfield: Pharmacology (medical)
Field: Medicine
Domain: Health Sciences
Open Access status: green
Awards: G1438067556, G1793559018, G179444772, G222496000, G2258400832, G238323396, G2511155013, G3434867832, Die bidirektionale Analyse der Beziehung zwischen subklinischer Arteriosklerose und der Depression (BiDirect), G4452206969, G4812287033, G5199629419, G5275296542, G648958512, G6711686236, G6733821374, G705501481, Analyse der Beziehung zwischen subklinischer Arteriosklerose und der Depression (BiDirect) (Anschlussvorhaben), G7341669135, DIALOG: Understanding Disorganisation: A Language-focused Global Initiative in Psychosis, G8087705, Geschlechtsunterschiede im alternden Gehirn - Muster, Mechanismen und Auswirkungen
OpenAlex ID: W7204890243