Two years of high-dose fish oil raised omega-3 levels in the brain but did not improve memory or thinking, or slow shrinkage of the hippocampus, in 365 older adults at elevated risk of Alzheimer’s disease, according to a randomized, double-blind, placebo-controlled trial at the University of Southern California (USC). The peer-reviewed results were published in eBioMedicine on June 18, 2026, and USC’s account of them was recirculated this week by ScienceDaily.
The trial, known as PreventE4 and registered as NCT03613844, ran at a single USC site from September 2018 to May 2024. It enrolled adults aged 55 to 80 who had no dementia, consumed less than 200 milligrams a day of DHA from their diet and had at least one risk factor for dementia. Of 739 people screened, 365 were randomized to 2 grams a day of docosahexaenoic acid (DHA), the main omega-3 in fish oil, or to placebo, the paper reports. Participants had a mean age of 66.4 years, 58 percent were women, 39 percent were Hispanic, and 47 percent carried the APOE ε4 gene variant, the strongest known genetic risk factor for late-onset Alzheimer’s.
The primary outcome was biochemical: the change at six months in the ratio of DHA to arachidonic acid in cerebrospinal fluid, measured in the 181 participants willing to undergo lumbar puncture. On that measure the supplement did what it was meant to do. The ratio rose by 0.17 in the DHA group and fell slightly in the placebo group, a difference of 0.19 (95% confidence interval, 0.16 to 0.21; p < 0.0001), and the effect was the same regardless of APOE ε4 status. USC’s announcement put the rise in cerebrospinal fluid DHA at about 17 percent.
Clinical outcomes did not follow. Over 24 months there were no differences between groups in cognitive performance or brain volumes, the authors reported. Scores on the RBANS cognitive battery rose by 2.76 points in the DHA group and 2.67 in the placebo group, a difference of 0.09 with a confidence interval spanning zero, and hippocampal volume declined by less than 1 percent a year in both groups with no significant difference, according to the paper and a summary in Healio. Adverse events were similar between groups and no serious adverse events were attributed to treatment. Dropout was 38 percent, mainly because of the COVID-19 pandemic; 225 participants completed the trial.
Dr. Hussein Yassine, director of the USC Center for Personalized Brain Health and the trial’s lead investigator, said in USC’s announcement that “our findings showed that fish oil supplements do not appear to protect brain health” in this population. In remarks reported by Healio, he added: “That suggests the issue is not simply dose or delivery.” The authors conclude that future research should prioritize understanding how the brain metabolizes DHA over further supplementation trials.
The trial was funded by the National Institute on Aging and the Alzheimer’s Drug Discovery Foundation, with additional National Institutes of Health grants listed in the announcement.
Why it matters
Americans spend more than $1 billion a year on fish oil supplements, the USC announcement says, partly on the strength of claimed brain benefits. Earlier supplement trials in people without dementia had mostly been negative, but it was unclear whether the omega-3 was reaching the brain at all, particularly in APOE ε4 carriers, who break down DHA faster, according to the paper’s background as summarized by Healio and News-Medical. This trial closes that gap: a high dose did reach the brain, in carriers and non-carriers alike, and still made no measurable difference to cognition or brain structure over two years.
The researchers do not conclude that omega-3s are useless. Yassine’s team suspects that nutrients may work differently in whole foods, where they interact with each other and with overall health, and points to earlier research linking a Mediterranean-style diet to lower Alzheimer’s risk; that is a hypothesis the trial did not test. “Staying healthy throughout life remains the most powerful tool we have for reducing Alzheimer’s risk,” Yassine said.
The caveats
The 38 percent dropout, driven by the pandemic, reduced the trial’s power to detect small effects, and those who withdrew were more likely to be Hispanic, to have less education and to have lower baseline cognitive scores, according to News-Medical’s summary of the paper. Participants were relatively young, well educated and cognitively healthy at the start, with little decline over two years in either group, so a benefit in people further along could not be ruled out. The study ran at one site, tested a single nutrient, and a two-year follow-up may be too short for a prevention effect to appear. Its clinical measures were secondary and exploratory; the trial was designed around a biochemical endpoint, which it met.
What to watch
Yassine said the team is studying how factors such as poor health, diet, genetics and age affect the brain’s use of omega-3s, and is working on medications intended to help the brain use them, according to the announcement.
This article is for general information and does not replace advice from a qualified clinician. Corrections: email the editor using the address on the Contact page.
