High-dose fish oil supplements got into the brains of older adults in a two-year clinical trial, but they did not improve memory, slow cognitive decline, or preserve a key memory-related brain region, according to researchers at the USC School of Medicine.
The result is a useful bucket of cold water for a familiar supplement claim. Docosahexaenoic acid, or DHA, is an omega-3 fatty acid found in oily fish including mackerel and sardines. It is involved in forming connections between brain cells, which is why it has long been pitched as a plausible brain-health nutrient. Plausible biology, however, is not the same thing as a working prevention strategy for Alzheimer’s disease.
Hussein Naji Yassine, director of the Personalized Brain Health Center at USC, said the trial does not support using fish oil supplements to prevent Alzheimer’s-related decline. He said omega-3s have a role in brain cell connections needed for cognition, but the study did not show that supplements protect brain health.
What the trial tested
Yassine and colleagues ran a randomized, double-blind, placebo-controlled study in 365 men and women ages 55 to 80 who rarely ate fish. All participants consumed less than 200 milligrams of DHA a day through food. Nearly half, 47 percent, carried the APOE ε4 allele, which the researchers described as the strongest genetic risk factor for late-onset Alzheimer’s disease.
Participants were assigned to take either 2,000 milligrams of DHA each day or a placebo for 24 months. The placebo was made from corn oil and soybean oil and matched the DHA supplement in appearance, smell, and taste. Participants and researchers did not know who received which product.
The trial first addressed a basic mechanistic question that supplement marketing tends to skate past: does swallowed DHA reach the central nervous system in measurable amounts? The researchers measured DHA in cerebrospinal fluid, the fluid around the brain and spinal cord. After six months, DHA concentrations rose 17 percent in the supplement group. The increase did not differ between APOE ε4 carriers and noncarriers, according to the USC team.
That finding matters because it closes one escape hatch. The negative result was not because DHA failed to show up where researchers could detect it.
No measurable cognitive benefit
After 24 months, participants took the Repeatable Battery for the Assessment of Neuropsychological Status, a standardized measure of memory and cognitive performance. The researchers found no significant difference between the DHA and placebo groups.
Brain structure showed the same pattern. The study found no significant difference in hippocampal volume changes between the groups. The hippocampus is central to memory and is used as an early biomarker in Alzheimer’s disease research.
The researchers offered several possible reasons why DHA reached the brain without producing measurable benefit. One involves calcium-dependent phospholipase A2, or cPLA2, an enzyme that may break down DHA before it can be incorporated into synaptic membranes, where DHA is thought to support cognition.
The team also pointed to cardiovascular risk factors among participants, including obesity, hypertension, and physical inactivity. Chronic inflammation linked with those conditions may have reduced any effect from adding a single nutrient. The group’s average age was 66, and participants had little cognitive decline during the study, which may have made a protective effect harder to detect.
The study also had limits. The researchers said 38 percent of participants dropped out before finishing, and the Covid-19 pandemic may have affected interpretation of the results. The trial was conducted at a single center, so the findings may not generalize to broader populations.
The USC team said future work will examine DHA metabolism in the brain, people with preclinical Alzheimer’s disease, more sensitive biomarkers such as plasma phosphorylated tau and neurofilament light chain, and treatment differences tied to gut microbiome composition and APOE genotype.
For now, the findings leave fish oil in a familiar place: biologically interesting, commercially popular, and not proven by this trial to prevent dementia. The researchers pointed instead to better-established risk-reduction measures, including regular physical activity, good-quality sleep, and a balanced diet.
This story draws on original reporting from WIRED.
