High-dose omega-3 supplements were not associated with improved memory or cognitive function in cognitively unimpaired older adults at high risk for dementia, a new clinical trial suggested.

While researchers found evidence of the omega-3 docosahexaenoic acid (DHA) in cerebrospinal fluid (CSF) — indicating the nutrient reached the brain — it didn’t translate to benefits in hippocampal volume or cognitive performance.

There was also no association with decreased brain cell loss in areas of the brain related to Alzheimer’s disease (AD), regardless of APOE epsilon 4 status.

“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,” lead investigator Hussein N. Yassine, MD, director of the Center for Personalized Brain Health, University of Southern California in Los Angeles, said in a statement.

The findings were published online on June 18 in eBioMedicine.

Unanswered Questions

Previous studies have shown no protective cognitive effects from low-dose DHA supplementation in older adults, but it was unclear if the results were influenced by insufficient dosing or a lack of brain penetrance.

To address that issue, researchers led a single-center, phase 2a study, enrolling 365 mostly White community-dwelling adults aged 55-80 years (mean age, 66.4 years; 58% female) with normal cognition and low omega-3 intake at baseline. About 47% were APOE epsilon 4 carriers, making them at an increased risk for AD.

Participants had at least one cardiovascular or dementia risk factor, such as obesity, hypertension, hyperlipidemia, or physical inactivity. Despite this, the study population was relatively healthy, with minimal baseline decline (median Mini-Mental State Examination score of 29 and median Montreal Cognitive Assessment-blind score of 20).

Researchers divided participants into two groups — those who agreed to undergo a lumbar puncture (LP; n = 181) for CSF collection and those who didn’t (no-LP; n = 184).

They randomly assigned all participants to receive either a supplement of high-dose DHA (2 g/d) or matched placebo for 24 months.

The primary outcome was change in the ratio of CSF DHA to arachidonic acid, a polyunsaturated omega-6 fatty acid, at 6 months, in the LP arm.

From MRI scans obtained at baseline and 24 months, investigators determined intracranial volume and total hippocampal volume. They also assessed cognitive function of subjects at baseline and follow-up using the Total Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) which tests five domains — language, attention, visuospatial/constructional abilities, and immediate and delayed memory.

About 38% of participants dropped out of the study, primarily due to COVID pandemic disruptions, leaving 225 participants who completed the trial.

Brain Penetrance, but No Benefit

At 6 months, the intervention group showed a 17% increase in CSF DHA levels, indicating brain penetrance, whereas the placebo group reported a decrease (mean change for DHA, 0.17 vs -0.02; P < .0001). The effect was consistent regardless of APOE epsilon 4 status.

At 24 months, there was no significant differences between the intervention and placebo groups in hippocampal volume, which declined minimally in both cohorts, or RBANS scores. APOE status didn’t modify the treatment response on total RBANS.

“The failure of high-dose DHA supplementation to modify clinical outcomes despite confirmed CNS delivery suggests that membrane phospholipid composition changes alone are insufficient,” the authors wrote.

They noted that DHA supplementation as monotherapy may be insufficient when multiple pathophysiologic processes drive neurodegeneration and alter the fate of DHA in the brain.

Factors such as poor health, dietary patterns, and genetic risks might affect how the brain processes omega-3s, said Yassine in the statement.

Adverse events occurred at about the same rate in both groups (40.3% in the DHA group vs 40.9% in the placebo group). Serious adverse events occurred in 2.8% of DHA participants vs 7.2% of the placebo groups.

The insights gleaned from the new study should redirect the field toward understanding mechanisms of brain DHA metabolism, and which populations, intervention durations, or combination approaches might yield measurable clinical benefits, the authors wrote.

As patients with early neurodegeneration may be more likely to demonstrate measurable decline than asymptomatic subjects, future trials may benefit from targeting these individuals, they added.

The study population was relatively young and highly educated and had minimal baseline cognitive or structural brain changes, so may not represent typical clinical prevention populations. Other study limitations were the single-center design and the relatively high drop-out rate.

The study was supported by the National Institutes of Health, National Institute on Aging, and the Alzheimer’s Drug Discovery Foundation. Study authors’ disclosures are available in the original article.