Depression has long been linked with a higher risk of dementia and Alzheimer’s disease, but the biological connection has remained unclear. New research now identifies a specific memory-related structure in the brain that appears to be smaller in people living with depression.
In a study published in Translational Psychiatry, scientists found reduced volume in part of the hippocampus, a region essential for memory, learning and spatial navigation. The work focused on older adults who currently showed no signs of cognitive impairment.
Targeting a key hippocampal region
The research team from the University of Southern California analyzed MRI and PET brain scans from more than 2,000 adults aged 50 to 90. Around one-third of these participants had a history of depression, allowing comparisons between depressed and non-depressed groups.
Rather than looking at the hippocampus as a single structure, the scientists examined its individual subregions. They identified a composite area called CA23DG, formed by the CA2 and CA3 subfields and the dentate gyrus, as being particularly affected in individuals with depression.
After adjusting for age, sex, body mass index and physical activity, CA23DG volume was significantly smaller in participants with depression. Other hippocampal regions, such as CA1 and the subiculum, did not show the same pattern in the initial analysis.
Alzheimer’s markers not driving the effect
Researchers then explored whether known Alzheimer’s risk markers could explain the hippocampal changes. They factored in brain levels of amyloid and tau proteins, as well as the APOE ε4 gene variant, a major genetic risk factor for Alzheimer’s.
The link between depression and reduced CA23DG volume remained largely unchanged after accounting for these markers. This suggests that the structural changes seen in CA23DG may arise through mechanisms distinct from classic Alzheimer’s pathology.
According to the authors, depression and Alzheimer’s disease might both affect memory, but potentially through different biological pathways in the hippocampus. This raises new questions about how mental health and neurodegeneration interact over time.
Mixed signals about antidepressant use
The team also examined antidepressant medication use among participants. When this factor was included, people taking antidepressants showed reduced volume not only in CA23DG but also in CA1, another key hippocampal subfield.
On the surface, this appears puzzling because treatments are expected to protect the brain by easing depressive symptoms. The authors note that people prescribed medication often have more severe or long-standing depression, which itself may drive greater brain changes.
Duration of depression emerged as another potential factor. Individuals who had lived with depression for longer periods, even when their current symptoms were milder, showed a stronger association with reduced CA23DG volume than those with more recent, acute episodes.
Correlation, not proof of causation
The researchers stress that their findings are correlational and cannot prove that depression or its treatment directly causes parts of the hippocampus to shrink. Medication effects are difficult to disentangle from the consequences of more severe illness.
Lead author Danielle Luu cautions that the study should not prompt patients to stop or alter prescribed antidepressants. Long-term, carefully designed studies following people before and after treatment will be needed to clarify whether medication, depression severity or other factors drive these structural changes.
Experts say the results add an important clue to understanding how mood disorders may influence brain aging. They also highlight the importance of early detection and sustained management of depression as part of broader strategies to protect cognitive health in older adults.
The study contributes to a growing body of evidence that depression is not only a mood disorder but is also associated with measurable changes in brain structure. Future research will aim to determine whether modifying depression risk or improving treatment can slow or reverse hippocampal alterations.
