Omega-3 Fatty Acids May Not Protect Cognition

Pauline Anderson

September 26, 2013

Intake of omega-3 fatty acids may not protect cognition, a new study suggests.

In contrast to some past research, researchers report that after adjustment for confounding factors, red blood cell (RBC) levels of omega-3 polyunsaturated fatty acids (PUFAs) were not significantly associated with baseline cognitive function or cognitive change over time in older, dementia-free women.

Some previous large observational studies did come to the same conclusion, and with these new results, the evidence that omega-3 fatty acids is not associated with cognitive protection is now "pretty consistent," said study author Robert Wallace, MD, professor, epidemiology and internal medicine, University of Iowa College of Public Health, Iowa City.

"We added some good-quality observational information," Dr. Wallace told Medscape Medical News.

However, because eating fish, nuts, and other foods rich in omega-3s has other health benefits, including possibly lowering heart disease risk, clinicians should not change their recommendations surrounding the intake of omega-3 fatty acids, said Dr. Wallace.

The study was published online September 25 in Neurology.

WHISCA Analysis

The study was a secondary analysis of data collected for the Women's Health Initiative Study of Cognitive Aging (WHISCA), a study within the WHI hormone therapy (HT) trials. In the HT trials, women aged 65 to 80 years who had undergone a hysterectomy were randomly assigned to estrogen or placebo and women who had not had a hysterectomy took estrogen plus progestin or placebo.

The current analysis included 2157 dementia-free participants whose first cognitive assessment took place a median of 3 years after HT randomization. They completed a battery of cognitive tests annually for a median of 5.9 years.

The annual WHISCA test battery included standard assessments in 7 cognitive domains: Finger Tapping Test for fine motor speed, Card Rotation Test for spatial ability, Benson Visual Retention Test for short-term visual memory, California Verbal Learning Test for verbal memory, Primary Mental Abilities Vocabulary test for verbal knowledge, letter and category fluency tests for verbal fluency, and Digit Span Forward and Backward Test for working memory.

Before WHI randomization, investigators obtained blood samples. RBC omega-3 PUFA content served as a biological marker of average omega-3 PUFA intake over the previous 1 to 2 months. In this analysis, the exposure of interest was the proportion of participants' RBC membranes composed of docosahexaenoic acid and eicosapentaenoic acid (DHA+EPA.)

The primary endpoints were the mean difference between the high and low DHA+EPA tertiles in cognitive performance at baseline and change over time in composite cognitive function and each of the 7 cognitive domains. Because of the number of cognitive domains included as endpoints, researchers used .01 as the critical value for statistical significance.

The study found that participants in the high DHA+EPA tertile exhibited better fine motor speed, verbal knowledge, and verbal fluency, but after full adjustment for factors such as age, race, income, body mass index, physical activity, smoking, and daily caloric intake, these associations were no longer statistically significant (fine motor ability, P = .04; verbal knowledge, P = .14; verbal fluency, P = .07).

Effect Null

While the overall effect "was rather null," the fact that the unadjusted analysis did uncover a possible association between omega-3 and motor speed and verbal fluency may suggest that certain parts of the brain or certain cognitive functions may be affected by this nutrient, said Dr. Wallace.

Although it's beyond the scope of the current study, it's possible, said Dr. Wallace, that people taking higher levels of omega-3s all their adult life may have a very different outcome.

The study found no other significant (P < .01) effects, and when cardiovascular disease, cerebrovascular disease, diabetes, hypertension, and depression were added to the model, the DHA+EPA effect estimates were almost unchanged.

As well, the study found no significant (P < .01) difference between the high and low DHA+EPA tertiles in the rate of change in any cognitive domain over the course of the follow-up.

Among the strengths of the study was that it had "good cognitive measures taken annually" and that omega-3 levels were from plasma, "which is sort of the net intake of omega-3s from any source," said Dr. Wallace. "It tells us something a little bit different than either dietary history, which is a very difficult commodity to measure, or dietary supplements."

A possible study limitation was that improper storage of blood samples may have led to degradation. Although this may be a potential source of bias, researchers adjusted for it and, as Dr. Wallace pointed out, "very good fatty acid chemists" carried out the work.

"We think that these are reflective of all-source intakes of omega-3 in the time frame. We felt that after adjustment, our results were actually conservative."

As well, APOE genotyping, which some research suggests might play a role in the protective association between omega-3s and cognitive function, was unavailable for WHISCA participants."It would have been helpful to have that information, but I don't know that it would have changed the ultimate result, even though it might have identified groups that are at greater or lesser risk within the general women population," said Dr. Wallace.

Another potential limitation was that the first cognitive tests were administered an average of 3 years after DHA+EPA exposures. Again, Dr. Wallace said he didn't think that this affected the results. "We measured cognitive function several times and people tend to keep their similar diets, so we had every reason to believe that whatever they were doing before, they were still doing."

The low rates of cerebrovascular disease, diabetes, and other cardiovascular risk factors in the study group may limit the generalizability of the results to other populations.

Results "Disappointing"

Invited to comment, Mimi Minh-Ngoc Dang, MD, instructor, neurology, Alzheimer's Disease and Memory Disorders Center, Baylor College of Medicine, Houston, Texas, said she wasn't surprised by the study results but was disappointed because preventive approaches, particularly achievable dietary changes, can have major public health implications.

"An increased dietary intake of omega-3 fatty acids is one such dietary approach. In the prevention of age-related cognitive impairment, as in the prevention of cardiovascular disease, consistent data are lacking from clinical and mechanistic studies of the benefits of n-3 fatty acids for both primary and secondary prevention."

Dr. Dang is not against continuation of omega-3 fatty acid supplements as they may carry other benefits. "I would say that there is no definite benefit of omega-3 fatty acids in the primary prevention of age-related cognitive decline, but there may be other cardiovascular benefits from omega-3 fatty acid supplements."

As Dr. Dang explained, omega-3 fatty acids can manifest anti-inflammatory effects that are similar to the mechanism of aspirin. When omega-3 fatty acids are included in the diet, EPA and DHA compete with arachidonic acid in several ways, with the net effect being a change in the hemostatic balance toward a more vasodilatory state, with less platelet aggregation.

Omega-3 fatty acids are also metabolized by means of lipoxygenase to yield another class of eicosanoids — the leukotrienes — again creating anti-inflammatory effects, she said.

The age difference in the current study groups may have contributed to the null effect, according to Dr. Dang. She noted that the high DHA+EPA group appeared to have more women 70 years of age and older at first WHISCA examination than the low group (577 of 719 vs 510 of 719 or 80.3% vs 70.9%).

"The general rate of progression among those with a diagnosis of mild cognitive impairment is estimated at 10% per year," she said. "The estimated prevalence of mild cognitive impairment in population-based studies ranges from 10% to 20% in persons older than 65 years of age."

The study was supported by the National Heart, Lung, and Blood Institute; National Institutes of Health; and US Department of Health and Human Services. Dr. Wallace has disclosed no relevant financial relationships.

Neurology. Published online September 25, 2013. Abstract

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