Researchers from the USC Mark and Mary Stevens Neuroimaging and Informatics Institute ( Stevens INI ) at the Keck School of Medicine of USC have found that depression is associated with smaller volume in a specific part of the hippocampus, a brain region essential for learning and memory.
The study, published in Translational Psychiatry , examined high-resolution brain scans from 2,009 cognitively healthy adults ages 50 to 90. Researchers found that participants with depression had smaller volumes in a hippocampal area encompassing the CA2, CA3, and dentate gyrus, collectively called the CA23DG. The association remained after researchers accounted for body mass index, physical activity, and several major biological indicators of Alzheimer's disease risk, including amyloid and tau proteins and the APOE ε4 genetic variant.
"Depression has long been associated with an increased risk of developing Alzheimer's disease, but we still do not fully understand the biological connection between the two," said Danielle Luu, lead author of the study and a PhD student in the Neuroscience Graduate Program at USC "By looking closely at the individual parts of the hippocampus, we identified a specific area that may be particularly sensitive to depression in older adults."
A closer look at the brain's memory center
The hippocampus plays a central role in forming and retrieving memories. Although it is often discussed as a single brain region, it is made up of several smaller sections, or subfields, that perform different functions and may respond differently to aging, depression, and neurological disease. Studying the hippocampus as a whole can obscure changes concentrated in only one of these subfields. For the new study, researchers used high-resolution MRI scans to measure three areas: CA1; the subiculum; and CA23DG, a combined region containing CA2, CA3, and the dentate gyrus. Each of these areas contributes to learning and memory in a different way. CA1 helps the brain recognize new information and connect it with what is already known. CA23DG plays a particularly important role in retrieving memories, distinguishing between similar experiences, and using partial information to reconstruct more complete memories. The subiculum serves as a major pathway for carrying information from the hippocampus to other parts of the brain.
Among 2,009 participants, 630 were classified as having depression based on their current symptoms or a previous diagnosis from a health care provider. The remaining 1,379 participants did not have depression. All participants were cognitively unimpaired, allowing the researchers to investigate brain differences that may appear before memory loss or other symptoms of cognitive decline.
The researchers found that depression was associated with smaller CA23DG volume but not with significant differences in the CA1 or subiculum.
"This study shows why it is important to look beyond the total size of the hippocampus," said Meredith N. Braskie, PhD , senior author of the study, assistant professor of neurology, and director of education at the Stevens INI. Depression was not related to smaller volume throughout the entire region. The association was concentrated in a particular set of subfields, giving us a more precise picture of how depression may relate to brain health during aging."
Distinct from key Alzheimer's risk factors
Because depression is associated with a higher likelihood of developing Alzheimer's disease, the researchers also examined whether the observed brain differences could be explained by established Alzheimer's risk factors. They used positron emission tomography, or PET, scans to measure amyloid and tau, two proteins that accumulate abnormally in the brains of people with Alzheimer's disease. They also assessed whether participants carried APOE ε4, a gene variant associated with increased Alzheimer's risk.
Amyloid, tau, and APOE ε4 didn't significantly change the relationship between depression and CA23DG volume. The results suggest that depression may relate to hippocampal structure through pathways that are at least partly distinct from these well-known features of Alzheimer's disease.
"These findings reinforce the importance of considering mental health as part of the broader picture of healthy brain aging," said Arthur W. Toga, PhD , director of the Stevens INI and the Ghada Irani Chair in Neuroscience at the Keck School of Medicine. "Understanding how depression relates to specific memory systems may help researchers identify people at risk, clarify the pathways connecting depression and dementia, and ultimately guide more personalized approaches to protecting brain health."
Antidepressant findings require further study
Within the group with depression, participants who reported taking antidepressant medication had smaller CA1 and CA23DG volumes than those who did not report using the medications. However, the researchers cautioned that the finding does not necessarily show that antidepressants caused the differences.
Information was not available about how long participants had experienced depression, how severe their symptoms were before beginning treatment, or how long they had taken medication. People prescribed antidepressants may have experienced more severe or longer-lasting depression, which could itself relate to hippocampal volume.
"In this study, we cannot separate potential effects of medication from the effects of the more severe depression that medications are prescribed to treat," Luu said. "Long-term studies that follow people before and after treatment will be essential for understanding these relationships. Our results should not be interpreted as a reason for anyone to change or discontinue prescribed medication."
The study's depression diagnoses and medication information were also based on participant reports rather than medical records. Future research will follow participants over time and examine depression history, symptom severity, medication type, dosage, and duration of treatment.
A diverse study of healthy aging
Data for the study came from the Health and Aging Brain Study–Health Disparities, or HABS-HD , a community-based research initiative examining Alzheimer's disease risk and resilience among Hispanic, non-Hispanic Black, and non-Hispanic White older adults. The study's diverse population and detailed brain imaging enabled the researchers to examine depression and brain aging in a substantially larger and more representative group than many previous studies.
The findings do not establish that depression causes hippocampal shrinkage or that the observed differences will lead to Alzheimer's disease. Instead, they identify a specific brain region for further investigation and underscore the value of integrating mental health into research on aging and dementia.
About the study
In addition to Luu, Braskie, and Toga, the study's authors are 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, and Kristine Yaffe, together with the HABS-HD Study Team.
The research was supported by the Office of the Director of the National Institutes of Health under award S10OD032285 and the National Institute on Aging under awards R01AG054073, R01AG058533, R01AG070862, P41EB015922, and U19AG078109.
