Summary: Researchers identified a specific structural change in the hippocampus linked with depression in older adults. High-resolution MRI scans from 2,009 cognitively unimpaired adults aged 50 to 90 showed that those with depression had significantly smaller volume in the CA23DG hippocampal subfield, a combined region made up of CA2, CA3 and the dentate gyrus.
Key Facts
- Selective subfield vulnerability: Depression in cognitively healthy older adults was associated specifically with smaller volumes in the CA23DG subfield (CA2, CA3 and dentate gyrus). The CA1 and subiculum did not show significant volume differences.
- Independent of core Alzheimer’s markers: The relationship between depression and reduced CA23DG volume remained after controlling for established Alzheimer’s biomarkers, including amyloid-beta, tau and the APOE ε4 genetic risk variant.
- Role of CA23DG in memory: CA23DG contributes to memory retrieval, pattern separation (discriminating similar experiences) and pattern completion (reconstructing whole memories from partial cues).
- Antidepressant observation: Within the depressed group, those reporting antidepressant use had smaller CA1 and CA23DG volumes than non-medicated peers; authors note this may reflect greater illness severity or duration rather than direct medication harm.
- Diverse cohort: The study used data from the HABS‑HD initiative, sampling Hispanic, non‑Hispanic Black and non‑Hispanic White older adults with high-resolution imaging.
Source: USC
Researchers at the USC Mark and Mary Stevens Neuroimaging and Informatics Institute (Stevens INI) found that depression is linked to reduced volume in a specific hippocampal subfield important for learning and memory.
Published in Translational Psychiatry, the study analyzed high-resolution MRI scans from 2,009 cognitively unimpaired adults aged 50 to 90. Compared with people without depression, participants with depression showed smaller volume in a hippocampal composite region that includes CA2, CA3 and the dentate gyrus, referred to as CA23DG.
The association persisted after adjusting for body mass index, physical activity and major biological indicators of Alzheimer’s disease risk, including brain amyloid and tau accumulation and the APOE ε4 genetic variant.
“Depression has long been linked to greater risk of Alzheimer’s disease, but the biological mechanisms remain unclear,” said Danielle Luu, lead author and PhD student in the Neuroscience Graduate Program at USC. “By examining distinct hippocampal subfields, we identified a specific area that appears particularly sensitive to depression in older adults.”
A closer look at the brain’s memory center
The hippocampus is critical for forming and retrieving memories, but it is not a single uniform structure. It contains several subfields with distinct functional roles and varying sensitivity to aging, mood disorders and neurodegenerative disease. Examining only total hippocampal volume can hide localized changes; this study used high-resolution MRI to measure three subregions: CA1, the subiculum, and a composite CA23DG (CA2, CA3 and dentate gyrus).
Functionally, CA1 supports encoding and linking new information with existing knowledge. CA23DG is especially important for retrieving memories, distinguishing overlapping or similar experiences (pattern separation) and reconstructing complete memories from partial cues (pattern completion). The subiculum serves as a major output route from the hippocampus to other brain regions.
Of the 2,009 participants, 630 met criteria for current or past depression based on symptoms or a previous clinical diagnosis; 1,379 were not depressed. All participants were cognitively unimpaired, allowing the researchers to investigate structural brain differences that may appear before clinical cognitive decline.
Depression was associated with smaller CA23DG volume but not with significant differences in CA1 or the subiculum, highlighting that effects of depression on hippocampal anatomy can be localized rather than diffuse.
“This study demonstrates why looking beyond total hippocampal size matters,” said Meredith N. Braskie, PhD, senior author and assistant professor of neurology. “The association with depression was concentrated in a particular set of subfields, giving a clearer picture of how depression may relate to brain health during aging.”
Distinct from key Alzheimer’s risk factors
Given the established link between depression and increased Alzheimer’s risk, the team investigated whether the observed subfield differences could be explained by classic Alzheimer’s markers. PET imaging measured brain amyloid and tau, and genetic testing assessed APOE ε4 carrier status.
Adjusting for amyloid, tau and APOE ε4 did not materially change the relationship between depression and smaller CA23DG volume. This suggests depression’s association with hippocampal structure may follow pathways at least partly independent of typical Alzheimer’s pathology.
“Considering mental health alongside biological markers is essential for understanding brain aging,” said Arthur W. Toga, PhD, director of the Stevens INI. “Pinpointing how depression affects specific memory systems may help identify people at risk and guide more targeted approaches to protect brain health.”
Antidepressant findings require further study
Within the depressed subgroup, those reporting antidepressant use had smaller CA1 and CA23DG volumes than those who did not report medication. The researchers cautioned this does not prove antidepressants cause structural changes; medication use often correlates with more severe or longer-standing depression, which itself may relate to hippocampal volume.
Information about duration and severity of depression, treatment history, medication type, dose and length of use was limited in this cross-sectional dataset. Longitudinal studies that follow people before and after treatment will be necessary to disentangle effects of illness severity and medication.
“These results should not be interpreted as a reason to stop prescribed medication,” Luu emphasized. “We cannot separate medication effects from the underlying severity of depression in this study.”
A diverse study of healthy aging
The research used data from the Health and Aging Brain Study–Health Disparities (HABS‑HD), a community-based initiative designed to examine Alzheimer’s risk and resilience among Hispanic, non‑Hispanic Black and non‑Hispanic White older adults. The large, diverse sample and detailed imaging improved the study’s ability to detect localized subfield differences linked to depression.
The findings do not prove that depression causes hippocampal shrinkage or that these differences will lead to Alzheimer’s disease. Rather, they highlight a specific hippocampal region for further investigation and reinforce the importance of integrating mental health into research on aging and dementia.
About the study
Authors include Danielle Luu, Meredith N. Braskie, Arthur W. Toga, Alicia M. Twisselmann, Victoria R. Tennant, Brandon J. Hall, Arjun Mahajan, Audrey Kim, Jamie Terner, Marylan L. Davison, Koral Wheeler, Christopher R.K. Ching, James Hall, Matthew T. Borzage, Leigh Johnson, Sid E. O’Bryant, Kristine Yaffe and the HABS‑HD Study Team.
Funding: Supported by the Office of the Director of the National Institutes of Health (award S10OD032285) and the National Institute on Aging (awards R01AG054073, R01AG058533, R01AG070862, P41EB015922, U19AG078109).
Key Questions Answered:
Q: Why analyze hippocampal subfields instead of total hippocampal volume?
A: Subfields have distinct memory functions and can be differentially affected by aging and disease. Measuring the whole hippocampus can mask localized atrophy such as the CA23DG reduction associated with depression.
Q: Does this prove depression causes brain shrinkage or Alzheimer’s?
A: No. The study reports a cross-sectional association between depression and smaller CA23DG volume; it does not establish causation, and the relationship appears at least partly independent of amyloid and tau pathology.
Q: Should patients stop antidepressants based on these findings?
A: No. Medication use in cross-sectional studies often reflects greater illness severity. The observed volume differences are more likely related to the underlying depression than to prescribed antidepressants.
Editorial Notes:
- This article was edited by a Neuroscience News editor.
- The journal paper was reviewed in full.
- Additional context was added by staff.
About this depression and memory research news
Author: Laura LeBlanc
Source: USC
Contact: Laura LeBlanc – USC
Image: The image is credited to Neuroscience News
Original Research: Open access. “Depression and hippocampal subfield volume in older adults” by Danielle Luu et al., Translational Psychiatry. DOI: 10.1038/s41398-026-04223-y
Abstract
Depression and hippocampal subfield volume in older adults
Depression is associated with a higher risk for Alzheimer’s disease, but the mechanisms linking them are not fully understood. The hippocampus is commonly affected in both conditions and was the focus of this study.
This work examined two questions: (1) how depression and antidepressant medications relate to hippocampal subfield volumes during normal aging, and (2) whether Alzheimer’s risk markers—amyloid, tau and APOE ε4—modify those relationships.
The study included 2,009 ethnically diverse, cognitively unimpaired adults aged 50 to 90 (630 with depression, 1,379 without). High-resolution MRI measured volumes of CA1, the subiculum and a composite CA23DG region (CA2, CA3 and dentate gyrus).
Depression was associated with smaller CA23DG volume independent of amyloid and tau pathology. Among those with depression, reported antidepressant use was associated with smaller CA1 and CA23DG volumes compared with non-medicated peers, a result that requires longitudinal study to interpret.