Docosahexaenoic acid (DHA), an omega-3 fatty acid found in abundance in oily fish such as mackerel and sardines, is thought to improve cognitive function by supporting connections between brain cells. However, it has never been conclusively demonstrated that DHA taken as a dietary supplement actually reaches the brain or provides measurable benefits against dementia.
Against this backdrop, a research team at the USC School of Medicine has published the results of a large, two-year clinical trial involving older adults at elevated risk of developing Alzheimer’s disease. The study found that while high-dose DHA supplements do indeed reach the brain, they did not improve memory or cognitive function, nor did they slow brain atrophy.
“Everyone hopes for a silver bullet to prevent Alzheimer’s disease, but we can’t say that fish oil supplements protect brain health,” said Hussein Naji Yassine, director of the Personalized Brain Health Center at USC. “While omega-3s play an important role in forming brain cell connections needed for cognition, our results do not support fish oil supplements as a preventive measure against Alzheimer’s.”
DHA Reached the Brain, But …
Yassine and his colleagues conducted a randomized, double-blind, placebo-controlled trial involving 365 men and women between the ages of 55 and 80 who rarely ate fish. Nearly half of the participants (47 percent) carried the APOE ε4 allele, the strongest genetic risk factor for late-onset Alzheimer’s disease. All participants consumed less than 200 mg of DHA per day through their diet.
Participants were randomly assigned to one of two groups. One group received a daily supplement containing 2,000 mg of DHA, while the other received a placebo for 24 months. The placebo consisted of a mixture of corn oil and soybean oil and was indistinguishable from the DHA supplement in appearance, taste, and smell. Neither the participants nor the researchers knew which treatment each person received.
The researchers first wanted to determine whether DHA actually reached the brain. Measurements of DHA levels in the cerebrospinal fluid, which surrounds the brain and spinal cord, showed that concentrations increased by 17 percent after six months in the DHA group. There was no difference between carriers and noncarriers of the APOE ε4 allele, providing direct evidence that high-dose DHA supplementation reaches the brains of cognitively healthy older adults regardless of APOE ε4 status.
The results were very different, however, when it came to cognitive function and brain structure. After 24 months, participants completed the Repeatable Battery for the Assessment of Neuropsychological Status, a standardized test of memory and cognitive performance. No significant differences were found between the DHA and placebo groups. Likewise, there were no significant differences in changes in hippocampal volume, a brain region critical for memory and an early biomarker of Alzheimer’s disease.
Why Didn’t It Work?
The researchers suggest several possible explanations for why DHA reached the brain but failed to produce measurable clinical benefits. One possibility involves an enzyme that disrupts DHA metabolism in the brain. When an enzyme known as calcium-dependent phospholipase A2 (cPLA2) becomes activated, it may break down DHA before it can be incorporated into synaptic membranes—the structures where DHA is thought to play its most important role in supporting cognitive function.
Another possible explanation is that many participants had cardiovascular risk factors such as obesity, hypertension, and physical inactivity. The chronic inflammation associated with these conditions may have blunted the effects of supplementation, making it difficult for a single nutrient to produce measurable benefits.
The researchers also note that the participants were relatively young, with an average age of 66, and experienced only minimal cognitive decline over the course of the two-year study. As a result, there may simply have been too little decline during the trial to detect any protective effect from DHA supplementation.
The researchers further point out that the Covid-19 pandemic may also have affected the interpretation of the results, as 38 percent of participants dropped out before completing the trial. In addition, because the study was conducted at a single center, caution is warranted when generalizing the findings to broader populations.
Going forward, the research team plans to focus on understanding how DHA is metabolized within the brain, conducting studies in people with preclinical Alzheimer’s disease, incorporating more sensitive biomarkers of neurodegeneration—such as plasma phosphorylated tau and neurofilament light chain—and exploring personalized treatment strategies based on gut microbiome composition and APOE genotype.
Rather than relying on dietary supplements to prevent dementia, the findings suggest that, at present, the most effective way to reduce the risk of developing Alzheimer’s disease may still be to focus on well-established lifestyle measures, including regular physical activity, adequate high-quality sleep, and a balanced diet.
This story originally appeared on WIRED Japan and has been translated from Japanese.
