The timeline of brain aging in major depression: A prospective study from before first-onset to established illness
- 1Institute for Machine Learning in Medicine with focus area psychiatry
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.
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BibTeX
@misc{konowski2026timeline,
title = {{The timeline of brain aging in major depression: A prospective study from before first-onset to established illness}},
author = {M. Konowski and A. Kraus and J. Goltermann and J. Ernsting and K. Mahjoory and L. Fisch and J. Spanagel and S. Wellms and D. Bedir and L. Altegoer and T. Borgers and S. Teckentrup and S. Papenbrock and A. S. Hildebrand and E. Ratnalingam and E. Meisenzahl and F. Herrmann and S. Meinert and E. J. Leehr and J. Hubbert and J. Krieger and H. Meinert and H. Meinert and T. Slump and I. Nenadic and A. Jansen and N. Javaheripour and F. Thomas-Odenthal and H. Jamalabadai and B. Straube and M. Hermesdorf and M. Richter and R. Helbok and X. Jiang and N. Opel and K. Berger and T. Kircher and U. Dannlowski and T. Hahn and N. R. Winter and R. Leenings},
howpublished = {medRxiv},
year = {2026},
month = aug,
doi = {10.64898/2026.08.29.26361710},
url = {https://www.medrxiv.org/content/10.64898/2026.08.29.26361710v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - The timeline of brain aging in major depression: A prospective study from before first-onset to established illness
AU - M. Konowski
AU - A. Kraus
AU - J. Goltermann
AU - J. Ernsting
AU - K. Mahjoory
AU - L. Fisch
AU - J. Spanagel
AU - S. Wellms
AU - D. Bedir
AU - L. Altegoer
AU - T. Borgers
AU - S. Teckentrup
AU - S. Papenbrock
AU - A. S. Hildebrand
AU - E. Ratnalingam
AU - E. Meisenzahl
AU - F. Herrmann
AU - S. Meinert
AU - E. J. Leehr
AU - J. Hubbert
AU - J. Krieger
AU - H. Meinert
AU - H. Meinert
AU - T. Slump
AU - I. Nenadic
AU - A. Jansen
AU - N. Javaheripour
AU - F. Thomas-Odenthal
AU - H. Jamalabadai
AU - B. Straube
AU - M. Hermesdorf
AU - M. Richter
AU - R. Helbok
AU - X. Jiang
AU - N. Opel
AU - K. Berger
AU - T. Kircher
AU - U. Dannlowski
AU - T. Hahn
AU - N. R. Winter
AU - R. Leenings
PY - 2026
DA - 2026/08/29
PB - medRxiv
DO - 10.64898/2026.08.29.26361710
UR - https://www.medrxiv.org/content/10.64898/2026.08.29.26361710v1
AB - 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.
ER -