For this study, researchers used a combination of models, including one with mice and another with human brain microvascular endothelial cells, to examine how long-term fish oil use might impact the brain.

“This project developed over several years and was motivated by a broader question,” Onder Albayram, PhD, associate professor in the Department of Pathology and Laboratory Medicine within the Department of Neuroscience at the Medical University of South Carolina, and lead author of this study, told Medical News Today.

“Fish oil is widely used and generally considered beneficial, yet there are also observations in other areas of medicine suggesting that its effects may vary depending on the biological context, particularly during periods of tissue repair,” Albayram explained.

“We wanted to understand whether similar context dependent effects might exist in the brain,” he detailed. “To do this, we needed a model where the brain is actively engaged in recovery over time. Repeated mild head injury provided a useful framework, because it involves a prolonged and often subtle repair process, with elements of resilience and vulnerability.”

“In that sense, the model allowed us to study how dietary factors such as fish oil interact with the brain’s recovery mechanisms,” he continued. “The study evolved step by step, with the findings guiding the next questions.”

At the study’s conclusion, researchers found that one specific omega-3 fatty acid in fish oil, eicosapentaenoic acid (EPA), was associated with a reduced repair capacity in the brain, potentially interfering with healing after a brain injury.

“This was one of the most important parts of the study because it helped us move from observation to mechanism,” Albayram said.

“In the mouse model, several findings pointed toward the neurovascular unit, especially the cerebrovascular endothelial cells, as a vulnerable site after repeated mild brain injury. These cells form the inner lining of the brain’s blood vessels and help regulate blood flow, metabolic exchange, barrier function, and tissue repair. The human brain has an enormous vascular network, so even subtle changes in endothelial function can have meaningful consequences over time.”

– Onder Albayram, PhD

“Based on the mouse data, we developed an in vitro model using human brain microvascular endothelial cells to ask a more focused question: could EPA directly affect the repair capacity of these cells under conditions that allow fatty acid use?,” he continued

“What we found was that EPA, but not DHA, reduced endothelial repair responses, including vascular network formation and wound healing capacity. That was significant because it mirrored the direction of the mouse findings and suggested that EPA may act directly on the vascular repair machinery, rather than being only a secondary marker of injury,” said Albayram.

Additionally, Albayram and his team also correlated long-term fish oil supplementation to vascular-associated accumulation of the protein tau in the cortex, as well as lower neurological and spatial learning.

“We observed vascular associated tau accumulation in the cortex, which is a recognized but still not fully understood feature in conditions such as chronic traumatic encephalopathy,” Albayram explained.

“In human postmortem studies, tau often accumulates around blood vessels, but it is difficult to determine how this develops over time or whether the vasculature plays an active role in shaping this pathology. Our findings suggest that the cerebrovascular system, including endothelial cells, may be more directly involved than previously appreciated,” he told us.

“Importantly, these vascular changes were accompanied by neurovascular uncoupling, meaning a disruption in the coordination between neuronal activity and blood flow,” he continued. “This was observed alongside deficits in spatial learning and memory, indicating that the vascular and metabolic changes were functionally relevant. Ultrastructural analyses further supported this, showing disruption within the neurovascular unit.”

“Together, these results suggest that under certain conditions, dietary factors may influence how the brain’s vascular system adapts to injury, and that this can be linked to both pathological features, such as tau accumulation, and measurable changes in cognitive function,” Albayram added.

MNT had the opportunity to speak with Dung Trinh, MD, internist for the MemorialCare Medical Group and chief medical officer of Healthy Brain Clinic in Irvine, CA, about this research.

Trinh, who was not involved in the study, commented that its findings do not mean that fish oil is broadly harmful, but they do challenge the assumption that all omega-3 supplements are automatically brain-protective.

“For patients with repeated mild head injuries, especially athletes, veterans, or people with recurrent falls, the finding that EPA may interfere with brain vascular repair is clinically important and worth paying attention to,” Trinh explained.

“Brain health is complex, and cognitive decline can come from many causes, including Alzheimer’s disease, vascular disease, traumatic brain injury, sleep problems, mood disorders, medications, and metabolic conditions. We need continued research so we can move beyond one-size-fits-all advice and develop more personalized strategies to protect memory, thinking, and long-term brain function,” he added.

Trinh advised readers not to panic about this study’s findings, and not to abruptly stop anything recommended by their physician.

“This study does not prove that fish oil causes brain damage in the general population,” he continued. “But if someone has a history of repeated concussions or head trauma, they should talk with their doctor about why they are taking fish oil, what dose they are taking, and whether their supplement is EPA-heavy.”