🎗️Depression Can Leave Scars in Areas of The Brain Linked to Memory

Can depression leave marks on the brain even before memory problems appear? A study of more than 2,000 adults found an association between depression and reduced volume in regions of the hippocampus, an area essential for memory. Researchers also investigated signs related to Alzheimer's disease and found that the association remained even when these factors were taken into account.

Depression doesn't just affect mood. Previous research has shown that it can be related to changes in some brain regions, especially those involved with memory and emotions. At the same time, people with depression seem to have a higher risk of developing Alzheimer's disease later in life.

But could these two conditions be related by changes that occur in the brain long before memory problems appear? This is precisely the question that the researchers investigated, focusing on the hippocampus, a structure fundamental to the formation and organization of memories.

To investigate this relationship, researchers studied 2,009 people between the ages of 50 and 90 who did not have cognitive problems. This is important because it allowed them to observe brain changes in people who still maintained their thinking and memory abilities. Among the participants, 630 had depression and 1,379 did not.

The group with depression was also separated according to whether or not they used antidepressant medication. Thus, scientists were able to compare not only people with and without depression, but also observe whether there were differences between depressed people who used antidepressants and those who did not.

The next step was to examine the brain with high-resolution magnetic resonance imaging. Instead of analyzing only the hippocampus as a single structure, the researchers were able to observe smaller parts within it. Among these regions were CA1, the subiculum, and a set formed by CA2, CA3, and the dentate gyrus.

This division is important because different parts of the hippocampus participate in processes related to the formation, storage, and retrieval of memories. The researchers calculated the volume of these regions to see if people with depression showed differences compared to those without depression.

But there was another important question: could these differences simply be a consequence of changes related to Alzheimer's disease?

To investigate this, the researchers also considered two proteins associated with the disease, called amyloid and tau, as well as a genetic trait known as APOE4, which is related to a higher risk of Alzheimer's. In this way, they were able to verify whether the relationship between depression and hippocampal volume remained even when these risk factors for Alzheimer's were considered.

The results showed an important difference. People with depression had a smaller volume in a region of the hippocampus formed by CA2, CA3, and the dentate gyrus, compared to people who did not have depression.

This association remained even after the researchers considered the presence of amyloid and tau proteins. In other words, within the conditions analyzed in the study, the difference observed in the hippocampus did not seem to be simply explained by the presence of these Alzheimer's-related changes.

Area of ​​the hippocampus circled in red

Among people with depression, another result appeared: those who used antidepressants had smaller volumes in two regions of the hippocampus, CA1 and the group formed by CA2, CA3 and the dentate gyrus, when compared to depressed people who did not use these medications. This, however, does not mean that the antidepressants caused the reduction in brain volume.

The study found an association and, due to its design, cannot determine whether the difference is related to the medication, the depression itself, the severity or duration of the illness, or other factors. The main finding is that depression was related to structural differences in hippocampal regions important for memory, even in people who did not yet have cognitive impairments.

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Depression and hippocampal subfield volume in older adults

Danielle Luu, 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, Arthur W. Toga, Sid E. O’Bryant, Kristine Yaffe, and Meredith N. Braskie for the HABS-HD Study Team

Translational Psychiatry. 14 July 2026

DOI:10.1038/s41398-026-04223-y

Abstract: 

Depression is associated with a higher risk for developing Alzheimer’s Disease (AD) [1], but the mechanisms that underlie the complex relationship between depression and AD remain largely elusive. The hippocampus is a region of the brain that is commonly affected by both AD and depression and serves as a focal point for our study. We aim to understand the relationship of 1) depression and antidepressant medications to hippocampal subfield volume during normal aging, and 2) whether AD risk, as measured by amyloid and tau pathology and APOE4 status, impacts these relationships. We studied 2009 ethno-racially diverse cognitively unimpaired older adults aged 50 to 90 years who either had depression (n = 630) or were not depressed (n = 1379). Participants with depression were further stratified by antidepressant medication usage. High-resolution MRI scans were used to calculate hippocampal subfield volumes that included the CA1, the subiculum, and a composite region that included the CA2, CA3, and the dentate gyrus (CA23DG). Having depression was associated with a smaller CA23DG, independent of amyloid and tau pathology in the brain. Within the subgroup of participants with depression, those who used antidepressant medications had smaller CA1 and CA23DG volumes than those who did not use these medications.