docosahexaenoic acid (DHA), An omega-3 fatty acid found in abundance in fatty fish such as mackerel and sardines is believed to improve cognitive function by promoting connections between brain cells. However, it has never been conclusively shown that DHA taken as a dietary supplement actually reaches the brain or provides measurable anti-dementia benefits.

In this context, a research team from the USC School of Medicine has published the results of a large two-year clinical trial involving older adults at high risk of developing Alzheimer’s disease. The study found that while high-dose DHA supplements did reach the brain, they did not improve memory or cognitive function or slow brain atrophy.

“Everyone is hoping 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 USC Center for Personalized Brain Health. “While omega-3s play an important role in forming brain cell connections necessary for cognition, our results do not support fish oil supplementation as a preventative 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 aged 55 to 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 odor. Neither the participants nor the researchers knew which treatment each person received.

First, the researchers wanted to determine if 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 were no differences 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.

However, the results were very different when it came to cognitive function and brain structure. After 24 months, participants completed the Repeatable Battery for 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 the volume of the hippocampus, a brain region critical for memory and an early biomarker of Alzheimer’s disease.

Why didn’t it work?

Researchers suggest several possible explanations for why DHA reached the brain but failed to produce measurable clinical benefits. One possibility involves an enzyme that alters DHA metabolism in the brain. When an enzyme known as calcium-dependent phospholipase A2 (cPLA2) is activated, it can 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, it is possible that there was simply too small a decrease during the trial to detect any protective effect of DHA supplementation.