The findings challenge long-standing assumptions that omega-3 supplements uniformly support brain health and recovery after injury.
"But in terms of neuroscience, we still don't know whether the brain has resilience or resistance to this supplement. That's why ours is the first such study in the field,” he said.
The study focused on eicosapentaenoic acid, or EPA, one of the primary omega-3 fatty acids found in fish oil supplements.
Researchers said EPA accumulated in the brains of mice during long-term supplementation.
The buildup of EPA in the mice’s brains appeared to disrupt vascular repair processes after repetitive brain injuries, making it hard for the injured brains to heal properly after the mild injuries.
The researchers reported that EPA exposure "reprograms endothelial metabolism, impairing vascular repair and remodeling, and added that it promotes "tauopathy and cognitive decline" following brain injury.
Tauopathy is a group of brain diseases in which abnormal tau proteins accumulate and damage brain cells, leading to problems with memory, thinking, and behavior.
In behavioral testing, mice receiving EPA-enriched diets performed worse on spatial learning and memory tasks after injury than animals on control diets, according to the study.
The research also found similar problems in the brains of people who had died with chronic traumatic encephalopathy, or CTE—a brain disease linked to repeated head injuries. Their brain tissue showed the same kinds of blood vessels and metabolism issues seen in the mice.
Researchers emphasized that the findings do not establish that fish oil supplements cause CTE or cognitive decline in humans. Much of the evidence came from mouse models, laboratory cell experiments, and tissue analysis.
The study also looked at another main omega-3, docosahexaenoic acid, or DHA. In lab tests, DHA did not harm blood vessel repair, unlike EPA.
Researchers said DHA is usually linked to brain health, while EPA acts differently, and its effects may depend on when and how much is taken. EPA's long-term impact on brain recovery is still unclear.
"I am not saying fish oil is good or bad in some universal way," Albayram said. "What our data highlight is that biology is context-dependent. We need to understand how these supplements behave in the body over time, rather than assuming the same effect applies to everyone."
The research was published in Cell Reports on April 29.