September 2014 Issue

Fish Oils and Cognitive Function
By William S. Harris, PhD
Today’s Dietitian
Vol. 16 No. 9 P. 21

Research suggests higher omega-3 intake leads to greater brain health.

“Fish is brain food.”

The origin of this bromide is unclear, but scientific support for this idea during both the sunrise and sunset years of life is growing.

Scientists began to link fish oils, which are rich sources of two omega-3 fatty acids—EPA and DHA—with brain health by observing that DHA is one of the two most plentiful fatty acids in the brain, and that it’s particularly enriched in the retina of the eye, an extension of the brain. If it’s there, it’s probably doing something.

Studies in animals and newborn babies have confirmed that DHA deficiency adversely affects visual function and certain learning behaviors.1,2 More recently, anecdotal stories of very high doses of fish oil being used to successfully treat traumatic brain injury and of animal experiments showing accelerated healing after spinal cord injury continue to build the evidence base for omega-3s playing a functional role in the central nervous system.3,4

When studies reporting a link between fish intake and dementia/cognitive function began to be published, and biomarker-based studies showed lower plasma/erythrocyte omega-3 levels in patients with cognitive dysfunction, the stage was set for randomized trials to prospectively test whether higher omega-3 intakes could forestall the development of dementia and Alzheimer’s disease. This article summarizes some of the high points in this journey, discusses some recent findings in which the author was involved, and concludes with suggestions for using fish oils in the prevention (treatment?) of dementia and Alzheimer’s. (Several reviews are available regarding this information.5-9)

Before examining the studies themselves, some background on how scientists study diet-disease relationships may be helpful.

There are two basic epidemiological approaches, both of which look for associations between the intake of nutrient X and disease Y and between blood levels of nutrient X (ie, biomarkers) and disease Y. Both of these can be studied cross-sectionally, that is, at one point in time (disease prevalence), or prospectively, where intake/biomarker levels are determined at one time point and disease development (incidence) is tracked longitudinally.

The strongest of these study designs typically is the prospective/biomarker approach, but even this can’t show that a deficiency of nutrient X causes the disease—association never proves causation—but this is considered good evidence of possible causation.

The way to study causation is with a randomized controlled trial, where nutrient X is given to one group of randomly selected people and a placebo to an identical group, and then both groups are followed over years for disease development. However, this is a drug model, and it has limitations when studying nutrients, which, by definition, already are present in the body at some level, while drugs aren’t. Thus, in nutrition research, randomized controlled trials and prospective/biomarker-based studies both should be viewed as providing strong evidence for diet-disease relationships.

When it comes to omega-3 fatty acids and dementia, all of these research approaches have been used, and the jury is still out on their relationship.

Fish and Omega-3 Intake
Conklin and colleagues conducted a cross-sectional/intake-based study involving a group of 55 men and women with a mean age of 45; the highest tertile of EPA+DHA dietary intake was associated with larger hippocampal volume.10 (Hippocampal atrophy is commonly observed before symptomatic impairment.11)

Another example is the Cardiovascular Health Study in which, of 2,465 participants (59% women, average age of 75), the reported intake of fatty, nonfried fish (those richest in EPA+DHA) was inversely associated with the presence of subclinical brain infarcts on MRI examination (ie, defined as ischemic lesions of 3 mm or less in diameter).12

The Prospective Investigation of the Vasculature in Uppsala Seniors study exemplifies the intake/prospective approach. The investigators tested the hypothesis that higher cognitive test scores and greater brain volume are associated with a higher vs. lower omega-3 fatty acid dietary intake. The dietary intake of EPA+DHA of 252 cognitively healthy elderly subjects aged 70 was determined by a seven-day food protocol.13

Five years later, the participants’ global cognitive function was examined and MRI was used to measure their brain volumes. The subjects’ intake of EPA+DHA at the age of 70 was positively associated with global gray matter volume and global cognitive performance score at the age of 75. However, intake wasn’t significantly associated with total brain, global white matter, or regional gray matter volumes. In other words, people who ate more fish had fewer infarcts.13

These studies suggest that more fish in the diet helps preserve brain health, but they don’t prove that fish—much less the omega-3 fatty acids in fish—provide this benefit since another component of fish could be beneficial, the foods people avoid in order to eat fish could be harmful, or people who eat fish may have other lifestyle habits that are protective.

Omega-3 Biomarkers
The biomarker-based approach also was used in the Cardiovascular Health Study, measuring both cross-sectional and prospective end points. In this study, 3,660 participants aged 65 and older had a brain MRI done and a blood sample taken at baseline. Five years later, 2,313 had another MRI done. Baseline blood DHA levels were inversely related to the presence of subclinical infarct volume and white matter grade at baseline, and they were inversely associated with worsening white matter grade over time.12

Two reports from the Framingham Heart Study have linked omega-3 biomarker levels with brain health. The first was a prospective study looking at DHA levels in 899 participants in the original cohort in Framingham who were aged 76, on average, when their blood was drawn, and they were free of clinical dementia. They were followed over the next nine years for the development of dementia or Alzheimer’s. Those in the highest quartile of DHA (levels associated with eating about three fish meals per week) were nearly one-half as likely to develop dementia or Alzheimer’s compared with those with lower levels.14

In the cross-sectional Framingham Offspring cohort (in which the author was involved), researchers compared red blood cell levels of EPA and DHA with MRI and cognitive markers of dementia risk in 1,575 dementia-free participants (aged 67±9).15 Participants with red blood cell DHA levels in the lowest quartile had lower total brain and greater white matter hyperintensity volumes.15 A lower level of red blood cell DHA and of EPA+DHA (the latter termed “the omega-3 index”16) also was associated with lower scores on tests of visual memory, executive function, and abstract thinking.15 Hence, lower red blood cell omega-3 levels were linked with smaller brain volumes and a vascular pattern of cognitive impairment even in those free of clinical dementia.15

Another study from our group, using the omega-3 index as a biomarker of omega-3 fatty acid status, involved data from the Women’s Health Initiative Memory Study. We examined the extent to which the omega-3 index had a protective association with domain-specific cognitive function. The cognitive domains examined were fine motor speed, verbal memory, visual memory, spatial ability, verbal knowledge, verbal fluency, and working memory. Postmenopausal women (n = 2,157, mean age of roughly 70) had blood drawn at baseline. Three years later, they underwent the first cognitive testing panel, which was repeated for the next six years. A higher omega-3 index was associated with better fine motor speed, verbal knowledge, and verbal fluency.17

However, after statistical adjustment for nine other factors, the independent relationships were lost. No significant differences were found between the high and low omega-3 index tertiles in the rate of cognitive change over time. Therefore, in this cohort of women free of dementia at enrollment, while there were some connections between omega-3 status and deficits in certain cognitive function domains, these relationships either were mediated by or otherwise associated with other lifestyle/physiological factors.17

Pottala and colleagues conducted another analysis from the same cohort and found a significant direct relationship between the omega-3 index measured at baseline and total brain volume measured by MRI eight years later.18 A higher omega-3 index was specifically correlated with greater hippocampal volume. We concluded that a lower omega-3 index may signal increased risk for hippocampal atrophy.
Other examples of biomarker-based studies that found significant associations between MRI metrics and omega-3 levels come from Bowman and colleagues and from Samieri and colleagues.19,20

Intervention Studies
Currently, there are no published studies attempting to demonstrate that omega-3 fatty acids can help reverse Alzheimer’s or dementia; prevention appears to be the only hope. Because of the typically slow development of Alzheimer’s and dementia and the inability to positively identify when the process begins, performing intervention studies to forestall disease development requires a long period of time and large numbers of subjects to achieve worthwhile results. To date, several trials have been conducted,21-26 but only one lasted more than two years (40 months); it used very low omega-3 doses and focused on patients with a history of coronary heart disease.23

In general, beneficial effects from omega-3 fatty acids have been seen for some end points related to cognitive function (eg, executive function, attention, anxiety) for some subgroups (eg, noncarriers of ApoE4 allele, mild cognitive impairment; see review by Cederholm and colleagues9), so there’s reason to persevere with larger and longer trials.

Research to date indicates there’s virtually no risk associated with increasing the typically low (about 150 mg/day) EPA+DHA intake in Americans to 250, 500, or even 1,000 mg/day (see international recommendations in Flock and colleagues27). This can be accomplished by eating more fish, preferably oily varieties, or taking omega-3 supplements (from fish or algal oils).28

Given the “smoke” seen across a spectrum of studies linking higher omega-3 intakes/status with improved cognitive function, it seems likely that there is a “fire” behind it.

— William S. Harris, PhD, is a professor of medicine in the University of South Dakota Sanford School of Medicine. He’s also president of OmegaQuant Analytics in Sioux Falls, South Dakota, and a senior research scientist at Health Diagnostic Laboratory in Richmond, Virginia.

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14. Schaefer EJ, Bongard V, Beiser AS, et al. Plasma phosphatidylcholine docosahexaenoic acid content and risk of dementia and Alzheimer disease: the Framingham Heart Study. Arch Neurol. 2006;63(11):1545-1550.

15. Tan ZS, Harris WS, Beiser AS, et al. Red blood cell ω-3 fatty acid levels and markers of accelerated brain aging. Neurology. 2012;78(9):658-664.

16. Harris WS, von Schacky C. The Omega-3 Index: a new risk factor for death from coronary heart disease? Prev Med. 2004;39(1):212-220.

17. Ammann EM, Pottala JV, Harris WS, et al. Omega-3 fatty acids and domain-specific cognitive aging: secondary analyses of data from WHISCA. Neurology. 2013;81(17):1484-1491.

18. Pottala JV, Yaffe K, Robinson JG, Espeland MA, Wallace RB, Harris WS. Higher RBC EPA+DHA corresponds with larger total brain and hippocampal volumes: WHIMS-MRI study. Neurology. 2014;82(5):435-442.

19. Bowman GL, Silbert LC, Howieson D, et al. Nutrient biomarker patterns, cognitive function, and MRI measures of brain aging. Neurology. 2012;78(4):241-249.

20. Samieri C, Maillard P, Crivello F, et al. Plasma long-chain omega-3 fatty acids and atrophy of the medial temporal lobe. Neurology. 2012;79(7):642-650.

21. Witte AV, Kerti L, Hermannstadter HM, et al. Long-chain omega-3 fatty acids improve brain function and structure in older adults. Cereb Cortex. 2013;Epub ahead of print.

22. van de Rest O, Geleijnse JM, Kok FJ, et al. Effect of fish oil on cognitive performance in older subjects: a randomized, controlled trial. Neurology. 2008;71(6):430-438.

23. Geleijnse JM, Giltay EJ, Kromhout D. Effects of n-3 fatty acids on cognitive decline: a randomized, double-blind, placebo-controlled trial in stable myocardial infarction patients. Alzheimers Dement. 2012;8(4):278-287.

24. Dangour AD, Allen E, Elbourne D, et al. Effect of 2-y n-3 long-chain polyunsaturated fatty acid supplementation on cognitive function in older people: a randomized, double-blind, controlled trial. Am J Clin Nutr. 2010;91(6):1725-1732.

25. Lee LK, Shahar S, Chin AV, Yusoff NA. Docosahexaenoic acid-concentrated fish oil supplementation in subjects with mild cognitive impairment (MCI): a 12-month randomised, double-blind, placebo-controlled trial. Psychopharmacology (Berl). 2013;225(3):605-612.

26. Quinn JF, Raman R, Thomas RG, et al. Docosahexaenoic acid supplementation and cognitive decline in Alzheimer disease: a randomized trial. JAMA. 2010;304(17):1903-1911.

27. Flock MR, Harris WS, Kris-Etherton PM. Long-chain omega-3 fatty acids: time to establish a dietary reference intake. Nutr Rev. 2013;71(10):692-707.

28. Harris WS, Dayspring TD, Moran TJ. Omega-3 fatty acids and cardiovascular disease: new developments and applications. Postgrad Med. 2013;125(6):100-113.