High-dose omega-3 pills did not protect memory in a 2-year trial

A two-year trial of high-dose omega-3 supplements, the nutrients many people take fish oil for, found no benefit for memory, thinking or brain structure in older adults at higher risk of Alzheimer’s disease.¹ The pills did raise omega-3 levels in the fluid around the brain, so the nutrient got where it was meant to go. But people who took it scored about the same on tests as people given a placebo (a dummy pill), and their brains looked the same on scans.¹

The study, led by researchers at Keck Medicine of USC, was published in the journal eBioMedicine in June.² New details from the lead researcher, reported by Healthline on October 29, add to what is known about who finished the trial and how much omega-3 levels rose.¹

What the trial did

The researchers enrolled 365 adults aged 55 to 80 who did not have dementia. Their average age was 66. All got little DHA from their diets and had at least one risk factor for dementia.¹ DHA (docosahexaenoic acid) is an omega-3 fat that forms part of the outer layer of brain cells and helps nerve cells communicate.³

Nearly half the volunteers (47%) carried APOE4, a gene variant tied to a much higher risk of Alzheimer’s later in life.³ Having it does not mean a person will get the disease, but it is the strongest known genetic risk factor for the common, late-onset form.³

Each person was randomly assigned to take either 2,000 milligrams of DHA a day or a dummy pill.¹ The trial was double-blind: neither the volunteers nor the researchers knew who got which.³ The lead researcher, Hussein Yassine, director of the USC Center for Personalized Brain Health, told Healthline that the supplement was not made from fish. It contained more than 90% DHA and about 1% EPA, the other main omega-3 in fish oil.¹

What was measured

The team first checked whether the omega-3 reached the brain. They measured DHA in the cerebrospinal fluid, the clear liquid that surrounds and cushions the brain and spinal cord.³ After six months, DHA in that fluid had risen by an average of 17% in the supplement group.³

Blood levels rose too. Over two years, the volunteers’ omega-3 index, a measure of EPA and DHA in red blood cells, went from 4.9% to 11%.¹ “That’s a massive increase, but that doesn’t translate into clinical outcomes,” Yassine told Healthline.¹ DHA reached the brain equally well in people with and without APOE4.¹

Memory and thinking were tested at the start and again after two years. People taking DHA did no better than those on the dummy pill.³ Brain scans showed the supplement did not prevent shrinkage of the hippocampus, a region deep in the brain that is central to forming memories and is often used as a marker of brain aging and Alzheimer’s risk.³

According to the study’s authors, earlier trials could not tell whether DHA failed to reach the brain or reached it without helping. Because the DHA got there in this trial, they say it answers that open question.¹

“We all wish there was a silver bullet for preventing Alzheimer’s, but our findings showed that fish oil supplements do not appear to protect brain health.”

That is how Yassine summed up the result in the university’s announcement.²

What it does not show yet

Of the 365 people who enrolled, only 225 completed the trial.¹ That is a large share of dropouts, and the sources do not explain why people left.

The trial was also short compared with the disease it is meant to prevent. “It’s also important to recognize that Alzheimer’s disease develops over decades, so a two-year study may not be long enough to determine whether DHA supplementation has any long-term preventive benefits,” said Dung Trinh, an internist at MemorialCare Medical Group who was not involved in the study.¹ Yassine said researchers tend to fall into two camps: some see the results as evidence that supplements do not work in isolation, while others argue a longer follow-up or sicker participants would be needed to answer the question.¹

The study also had a narrow focus. It looked at older adults who rarely ate fish and had higher Alzheimer’s risk, and tested one specific high-dose DHA supplement. It did not test eating fish, a Mediterranean-style diet, or fish oil used for other medical reasons, such as managing blood fats under a doctor’s care.⁴ The results do not rule out benefits from eating fish or following a Mediterranean-style eating pattern.⁴

Who is behind it

The study was supported by the US National Institutes of Health and the Alzheimer’s Drug Discovery Foundation.⁴ Other USC authors include clinical psychologist Lina D’Orazio, psychiatry professor Lon Schneider, neurology research professor Michael Harrington and neurology assistant professor Meredith Braskie.⁵

Yassine’s team says it is now trying to understand why omega-3 can reach the brain without improving brain health, and is working to develop medications that may help the brain make better use of these nutrients.² The sources do not say whether any of the authors have financial ties to such products.

Yassine pointed to how the body handles omega-3s. He said obesity, smoking and a lack of exercise can all reduce how much omega-3 gets into the brain, and that fish and some fish oils may also contain other nutrients such as lutein, vitamin E and selenium.¹ Based on their earlier work, the researchers believe omega-3s may work better as part of a Mediterranean-style diet than in a standalone supplement.² That idea was not tested in this trial.

How it fits the field

Omega-3 supplements are widely used. In a 2017 to 2018 US federal survey, 21.8% of adults aged 60 and older said they had taken one in the past 30 days, according to the Centers for Disease Control and Prevention.¹ Americans spend more than $1 billion a year on fish oil supplements, partly because of hoped-for brain benefits.²

The new result is not the first of its kind. A 2010 trial in England gave 867 people with an average age of 75 either fish oil (200 mg EPA plus 500 mg DHA) or olive oil for two years and found no significant differences in tests of reaction time, spatial memory or processing speed.⁶

A separate observational study, which used data from the Alzheimer’s Disease Neuroimaging Initiative rather than a controlled trial, went further. It found omega-3 supplement use was linked with faster decline on several thinking tests in older adults.⁷ Its authors wrote that omega-3 use “may be associated with accelerated cognitive decline,” but that kind of study can show a link, not a cause, since people who choose supplements may differ in other ways.⁷ The USC trial did not report any harm; it found no difference between groups.¹

Trade and nutrition outlets have framed the USC trial as a challenge to the use of omega-3 supplements as a preventive brain health product.⁸ One noted that supplement claims are often built on observational research, while a randomized trial can more directly test whether a pill does what is expected.⁴

What to watch next

The open questions are now about how the brain uses omega-3, not whether it gets there. Yassine’s team is studying whether poor health, diet, genetic risk and age change the brain’s ability to absorb and use these fats.² Watch for that work, any drug the group develops to help the brain use omega-3s, and longer trials in people at risk, which some researchers say are needed to settle whether supplements could matter over decades.¹

The researchers also stressed that, outside the scope of the study, overall healthy living, including regular exercise, quality sleep and a balanced diet, remains in their view the strongest tool for reducing Alzheimer’s risk.²