Depression may be linked to subtle differences in a part of the brain that helps people form and retrieve memories, according to a large study of older adults.
Researchers at the University of Southern California found that people with depression had a smaller volume in one specific section of the hippocampus.
The hippocampus is a small structure deep inside the brain that is essential for learning and memory. It helps people store new experiences, recall past events and tell similar memories apart.
Scientists are especially interested in the hippocampus because it is affected by both aging and Alzheimer’s disease. Depression has also been linked in previous research to a higher risk of developing dementia later in life, although the reasons for this connection remain uncertain.
The new study was carried out by researchers from the USC Mark and Mary Stevens Neuroimaging and Informatics Institute at the Keck School of Medicine of USC. The findings were published in the peer-reviewed journal Translational Psychiatry in 2026.
The researchers examined detailed brain scans from 2,009 adults between the ages of 50 and 90. Importantly, all participants were considered cognitively healthy, meaning they did not show the memory and thinking problems normally used to identify cognitive impairment.
Among the participants, 630 were classified as having depression based on current symptoms or a previous diagnosis reported by the participant. The other 1,379 participants were not classified as having depression.
Rather than measuring only the total size of the hippocampus, the researchers examined smaller sections within it. This matters because the hippocampus is not one uniform structure, and its different parts perform somewhat different jobs.
The team measured three areas called CA1, the subiculum and CA23DG. CA23DG combines areas known as CA2 and CA3 with the dentate gyrus, all of which are involved in important memory processes.
CA1 helps the brain recognize and process new information and connect it with information that is already stored. The subiculum acts partly as an important route through which information leaves the hippocampus and travels to other areas of the brain.
CA23DG has important roles in recalling memories and distinguishing between experiences that are similar. It also helps the brain rebuild a fuller memory when only part of the original information is available.
The researchers found that people with depression had smaller CA23DG volumes than people without depression. They did not find the same significant relationship in CA1 or the subiculum.
This suggests that depression may not be linked to shrinkage across the entire hippocampus. Instead, the association appears to be concentrated in a more specific part of the brain’s memory system.
Lead author Danielle Luu, a doctoral student at USC, said examining individual parts of the hippocampus allowed the researchers to identify an area that may be particularly sensitive to depression in older adults. Looking only at the whole hippocampus could have hidden this more focused pattern.
The researchers also wanted to know whether the difference could simply be explained by factors connected with Alzheimer’s disease. They therefore examined several of the best-known biological signs and risk factors for the condition.
These included amyloid and tau, two proteins that can build up abnormally in the brain during Alzheimer’s disease. The team also considered APOE ε4, a genetic variant known to increase a person’s risk of developing Alzheimer’s.
Even after accounting for these factors, the relationship between depression and smaller CA23DG volume remained. The association also remained after researchers considered body mass index and physical activity.
This is an important finding because it suggests that the brain difference linked to depression may not simply be a result of the major Alzheimer’s-related factors measured in the study. Depression could be connected to hippocampal structure through other biological pathways.
However, the study does not show that depression causes this brain area to become smaller. Because the researchers examined associations at a particular period rather than proving a chain of cause and effect, it is also possible that pre-existing brain differences influence vulnerability to depression.
The researchers also examined antidepressant use. Among people with depression, those who reported taking antidepressants had smaller CA1 and CA23DG volumes than those who were not taking these medicines.
That finding needs especially careful interpretation. The study cannot show that antidepressants caused the smaller brain volumes because people taking medication may have had more severe or longer-lasting depression in the first place.
The researchers did not have complete information about how long participants had experienced depression, how severe it had been before treatment, or how long and at what dose they had used antidepressants. They stressed that the findings are not a reason for people to stop or change prescribed medication.
Another strength of the research was the population studied. The data came from the Health and Aging Brain Study–Health Disparities, which includes Hispanic, non-Hispanic Black and non-Hispanic white older adults and is designed to improve understanding of Alzheimer’s risk and healthy aging across diverse communities.
Overall, the study provides an important clue rather than a final explanation. Its large sample and detailed brain scans strengthen the finding that depression is associated with a specific hippocampal region, but the research cannot establish which came first or whether the difference predicts future dementia.
Long-term studies that repeatedly scan people’s brains while tracking depression, treatment and memory will be particularly valuable. They could reveal whether CA23DG changes over time, whether successful treatment affects it, and whether these differences help identify people who later develop cognitive problems.
For now, the findings reinforce the idea that mental health and brain aging should not be studied separately. Depression appears to have a measurable relationship with part of the memory system, but much more research is needed before scientists can say what that relationship means for an individual person’s future brain health.
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Source: University of Southern California.
