Fish and long-chain omega-3 fatty acids, DHA & EPA

DHA and other long-chain omega-3 polyunsaturated fatty acids are found in fatty fish and fish oil. Supplementation does not improve cognition in most elderly people but could benefit people with cognitive impairment that is less severe than dementia. Although the evidence has surprising discrepancies, people who have more of these fatty acids in their blood appear less likely to develop Alzheimer’s. 

EFFICACY
Likely
with   Limited  evidence
SAFETY WHEN
USED AS DIRECTED
Very likely
with   Strong  evidence

Omega-3 fatty acids are essential for brain and body health.  They are a family of polyunsaturated fatty acids sometimes referred to as n-3 fatty acids, a term that describes their shared chemical structure.  The omega-3 fatty acids vary in length from the shorter alpha-linolenic acid (ALA) to the long-chain eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA).  Our bodies are not very good at converting short-chain to long-chain omega-3 fatty acids so eating ALA doesn’t usually raise DHA levels[1].  We also cannot make omega-3 fatty acids from scratch – we have to consume them.

Omega-3 fatty acids are distinct from omega-6 polyunsaturated fatty acids.  Some research suggests that diets with a high ratio of omega-6 to omega-3 fatty acids could lead to inflammation, disease, and dementia [2,3]. However, omega-6 fatty acids are essential nutrients and reducing their intake is not necessarily a healthy choice [4].

Here, we focus on the evidence for fish and the long-chain omega-3 fatty acids, DHA and EPA, rather than the short-chain fatty acids like ALA. 

Did you know? Although fish oil is the most common source of DHA and long-chain omega-3 fatty acids, it is the algae, not the fish, which create these fatty acids. Fish often contain high amounts of omega-3 fatty acids because they or their prey have eaten the algae. 

Omega-3 fatty acids can be consumed through fish, supplements derived from fish or algae, foods enhanced with omega-3, and FDA-approved drugs.       

Food: The most common food source of DHA is dark-meat fin-fish like tuna, salmon, mackerel, herring, and sardines.  DHA and EPA are found in much lower levels in shellfish, tilapia, and fried fish [5]. The only vegetarian source of DHA is specific types of algae and related supplements.  Some plants contain short-chain fatty acids like alpha-linolenic acid but not DHA or EPA. To substantially raise the levels of DHA in the blood, most people need to consume DHA directly [1].

Although some studies report that better cognitive function in aging is associated with fatty but not lean fried fish or shellfish, other studies report that the intake of fish in general rather than fish specifically high in DHA has been most strongly associated with a decreased risk of dementia [6, 7]. In other words, fish may exert a benefit completely apart from DHA.

Supplements and food with added supplements: DHA and/or EPA supplements from fish oil or algae are widely available although their quality and content varies [8].  Currently, no substantial scientific evidence exists to show that different supplements are more or less effective to potentially protect the brain from disease. The results from trials on specific supplements are discussed below.

Resources to understand the reliability of supplements, such as whether they contain toxins or contain the ingredients on their label, are reviewed below. DHA is prone to oxidation so some sources recommend that it be refrigerated or co-delivered with antioxidants but we are not aware of studies that have compared the biological effects of these different formulations.

FDA-approved drugs: Doctors can prescribe pharmaceutical sources of DHA and EPA, like Lovaza™, Vascepa™, and Epanova™. These drugs are reliable high-dose sources that have been rigorously tested and purified. However, for the purposes of cognitive aging and dementia, there is no evidence yet that these drugs are more or less likely to help the brain than other common sources. Vascepa contains only EPA while Lovaza and Epanova contain a combination of DHA and EPA in different chemical forms.

Dose: The dose of DHA that is most likely to benefit the brain is not known thanks to the diversity of results and design of available studies. The dose would likely fall within 180 to 2000 milligrams (mg) per day. Within this range, we don’t yet know whether the higher doses could provide extra benefit to the brain.  

In 2009, the average American consumed between 60 and 80 milligrams per day of DHA and between 20 and 30 mg per day of EPA (NHANES 2009-2010). In one respected observational study, Americans who consumed slightly more than this (180 mg per day from 2 to 3 servings of fatty fish per week) were 47% less likely to develop dementia over the next 9 years [9]. However, across the many observational studies that have tracked dementia risk with fish and/or DHA intake, no specific ideal dose has emerged and, in general, the intake of DHA and EPA in general has been less often linked to brain health than the intake of fish itself [6]. In clinical trials, DHA supplements of 400 to 2000 milligrams per day have been tested with varying but very limited success at improving cognitive function in older people [10], with no specific dose yielding a greater chance of success [11].

Likely prevents dementia, based on limited evidence.

No clinical trials have been sufficiently large and long enough to test whether DHA supplements or fish can reduce the risk of developing dementia per se. Supplementation does not appear to improve cognitive function in elderly people [12], even with a 5 year treatment with daily 350 mg of DHA and 650 mg of EPA [13]. However, some improvement has been seen in randomized trials on people who have cognitive impairment that is not severe enough to be considered dementia [11], for example with a 900 mg DHA supplement taken daily in older people with age-related memory impairment [14].

People who eat fish every week or who have higher DHA levels in their blood have had a lower risk of developing dementia or specific signs of brain aging in many studies [7, 15]. However, a pattern of reduced dementia risk has not been seen in all studies [7, 16].

APOE4 carriers: People who carry the ApoE4 genetic risk factor for Alzheimer’s disease may be less likely to benefit from DHA.  Several though not all observational studies report a protective association only in people who do not carry the E4 allele (reviewed in [7, 16]).  Similarly, in a clinical trial, DHA did not significantly help Alzheimer’s patients overall but it did appear to benefit patients who do not carry the APOE4 allele [17]. The E4 allele changes how the body and brain processes long-chain omega-3 fatty acids [18-20], which may partially contribute to the sometimes inconsistent evidence on whether these fats protects the brain from aging and dementia. Scientists are investigating if higher doses of DHA might have more benefit in E4 carriers. To learn more about what APOE means to your health, visit our  APOE information page.

Unlikely to benefit most people with dementia; possibly slows decline in people with mild cognitive impairment.

According to a 2012 meta-analysis of 10 randomized trials, long-chain omega-3 fatty acid supplementation is not likely to benefit Alzheimer’s patients but might yield some modest cognitive benefits in people with mild cognitive impairment [11], a subset of whom may progress to dementia. Some scientists believe that this evidence suggests that Alzheimer’s must be treated as early as possible.

More recent trials with various formulations have been mixed. A low dose daily treatment of 180 mg DHA plus 120 mg EPA had no benefit to elderly patients whether their cognition was normal or impaired [21]. A treatment of phosphatidylserine enriched with DHA (equivalent to roughly 100 mg per day) given to elderly people with mild memory impairment was reported to improve some aspects of their abilities (sustained attention and memory recognition) although other aspects of cognition and memory were not affected [22]. A very small trial suggested that omega-3 fatty acids given in combination with alpha lipoic acid for a full year slowed cognitive and functional decline, a benefit to Alzheimer’s patients [23]. Souvenaid™, a medical food available in Europe that contains DHA and EPA plus a variety of other nutritional components, has improved some symptoms in patients with Alzheimer's disease or frontotemporal dementia in small trials [24-26] but did not slow the cognitive decline in Alzheimer’s patients in another larger study [27]

APOE4 carriers: People who carry the APOE4 genetic risk factor for Alzheimer’s disease may be less likely to benefit from DHA. In a clinical trial, DHA treatment did not benefit Alzheimer’s patients overall but possibly improved cognitive function specifically in patients who did not have the APOE4 genotype [17]. To learn more about what APOE means to your health, visit our APOE information page.

Unknown, based on very limited evidence.

There is no consistent scientific evidence that raising DHA intake can slow the rate of aging per se [10]. However, omega-3 fatty acids can sometimes reduce inflammation [28], a driving factor for a variety of diseases. Omega-3 fatty acids can protect against vascular disease and possibly the risk of death from cardiovascular disease [29, 30] and some cancers [31, 32], although the evidence is inconclusive. Omega-3 fatty acids may also help to treat depression, particularly when the treatment contains more EPA than DHA and the omega-3 fatty acids is given in combination with other treatments [33].

DHA is a major building block of the brain that is critical for healthy development and function.  Indeed, a woman’s ability to create DHA from the shorter-chain omega-3 fatty acid ALA is increased during pregnancy [1]. In adults, researchers have identified a variety of potential ways in which DHA may protect or improve brain function.  For example, DHA may reduce inflammationincrease the birth-rate of new neurons in the adult brain, generate other protective chemicals like neuroprotectin D1, increase the fluidity of cell membranes, alter signaling pathways inside cells, and protect against the beta-amyloid and tau pathways that are believed to drive Alzheimer’s disease [16, 34].  

EPA is another long-chain omega-3 fatty acid that may also improve brain function although its protective properties are far less established [7].  Both EPA and DHA could also protect the brain indirectly by protecting the cardiovascular system [35] because vascular problems contribute to dementia in many older adults.  Protecting cardiovascular health may be one of the best strategies to protect against dementia in old-age [36].  

A meta-analysis of randomized trials strongly suggests that omega-3 fatty acids can help treat depression and depressive symptoms in many people, particularly if more EPA than DHA is given [33]. Treating depression might in turn protect the brain from dementia, although the evidence for this is not conclusive [37].

Fish contain nutrients beyond DHA and EPA that might benefit health. For example, it can be an excellent though varied source of lean protein, selenium, and vitamins A, D, and B12 [7].

Very likely safe, based on strong evidence.

NOTE: This is not a comprehensive safety evaluation or complete list of potentially harmful drug interactions. It is important to discuss safety issues with your physician before taking any new supplement or medication.

Long-chain omega-3 fatty acids are well-tolerated and generally recognized as safe at doses below 3 grams per day. They are one of the most widely consumed nutraceuticals in the Western world and they have been studied extensively for cardiovascular health and depression. These compounds may improve aspects of health ranging from cardiovascular disease, risk of death from cancer, age-related macular degeneration, Crohn’s disease, depression, and ADHD. However, doses higher than 3 grams per day may cause harm [38].

A meta-analysis of randomized trials reported that omega-3 fatty acids have not caused an increased risk of health problems, with the most likely side effect being gastrointestinal disturbances [39]. Omega-3 fatty acids were long-suspected to raise the risk of major bleeding, particularly in older adults. However, recent reviews of the clinical research argue that that concern may not be warranted and that omega-3 fatty acids will not raise the risk of bleeding, although people who have a high risk of bleeding have not generally been studied and some doctors may choose to err on the side of caution [39,40].

  • Discuss your options and choices with your health care providers, particularly if you are prone to gastrointestinal discomfort or bleeding.  
  • Do not supplement beyond 3000 mg (3 grams) per day of DHA and EPA combined unless under medical supervision [38]. Moderate doses such as 180 to 2000 mg per day have more scientific evidence for both safety and possible protection from dementia
  • Instead of supplementation, consider including one to three servings of fatty fish in your weekly diet, since these fish can have health benefits beyond omega-3 fatty acids. For a guide to mercury and other toxin levels in different fish, check out the seafood guides developed by Natural Resources Defense Council and other non-profits.

People may respond differently to omega-3 fatty acids based on their genetics, age and other factors. Ongoing research should help identify which people are more likely to benefit from consuming more omega-3 fatty acids and which type of omega-3 fatty acids. 

Several clinical trials are underway to provide more information on whether long-chain omega-3 fatty acids may protect against dementia or cognitive decline in elderly people. These include:

  • EPOCH trial in healthy older people (completed but not published as of August 2015)
  • VITAL study in healthy people over 65 (scheduled completion in 2016)
  • MAPT study in frail elders (scheduled completion in 2014)

Clinical trials are also testing whether long-chain omega-3 fatty acids can protect the brain from sports-related concussions in pediatric or college-level athletes NCT01903525, NCT01814527 and from post-traumatic stress disorder (NCT00644423) or traumatic brain injury (NCT01515917) in veterans.

Here is a list of resources of information that can assist you when making decisions about omega-3 fatty acid sources and/or supplements.

1              Burdge, G. C. & Calder, P. C. Conversion of alpha-linolenic acid to longer-chain polyunsaturated fatty acids in human adults. Reprod.Nutr.Dev. 45, 581-597, doi:10.1051/rnd:2005047 [doi];r5505 [pii] (2005).

2              Simopoulos, A. P. The importance of the omega-6/omega-3 fatty acid ratio in cardiovascular disease and other chronic diseases. Exp.Biol.Med.(Maywood.). 233, 674-688 (2008).

3              Loef, M. & Walach, H. The omega-6/omega-3 ratio and dementia or cognitive decline: a systematic review on human studies and biological evidence. Journal of nutrition in gerontology and geriatrics 32, 1-23, doi:10.1080/21551197.2012.752335 (2013).

4              Harris, W. S. et al. Omega-6 fatty acids and risk for cardiovascular disease: a science advisory from the American Heart Association Nutrition Subcommittee of the Council on Nutrition, Physical Activity, and Metabolism; Council on Cardiovascular Nursing; and Council on Epidemiology and Prevention. Circulation. 119, 902-907 (2009).

5              Chung, H. et al. Frequency and type of seafood consumed influence plasma (n-3) fatty acid concentrations. J.Nutr. 138, 2422-2427 (2008).

6              Kim, D. H. et al. Seafood Types and Age-Related Cognitive Decline in the Women's Health Study. The journals of gerontology. Series A, Biological sciences and medical sciences 68, 1255-1262, doi:10.1093/gerona/glt037 (2013).

7              Huang, T. L. Omega-3 fatty acids, cognitive decline, and Alzheimer's disease: a critical review and evaluation of the literature. J.Alzheimers.Dis. 21, 673-690 (2010).

8              Zargar, A. & Ito, M. K. Long chain omega-3 dietary supplements: a review of the National Library of Medicine Herbal Supplement Database. Metab Syndr.Relat Disord. 9, 255-271 (2011).

9              Schaefer, E. J. et al. Plasma phosphatidylcholine docosahexaenoic acid content and risk of dementia and Alzheimer disease: the Framingham Heart Study. Arch.Neurol. 63, 1545-1550 (2006).

10           Dacks, P. A., Shineman, D. W. & Fillit, H. M. Current evidence for the clinical use of long-chain polyunsaturated n-3 fatty acids to prevent age-related cognitive decline and Alzheimer's disease. J Nutr Health Aging 17, 240-251, doi:10.1007/s12603-012-0431-3 (2013).

11           Mazereeuw, G., Lanctot, K. L., Chau, S. A., Swardfager, W. & Herrmann, N. Effects of omega-3 fatty acids on cognitive performance: a meta-analysis. Neurobiol.Aging. 33, 1482-1429 (2012).

12           Sydenham, E., Dangour, A. D. & Lim, W. S. Omega 3 fatty acid for the prevention of cognitive decline and dementia. Cochrane.Database.Syst.Rev. 6:CD005379., CD005379 (2012).

13           Chew, E. Y. et al. Effect of Omega-3 Fatty Acids, Lutein/Zeaxanthin, or Other Nutrient Supplementation on Cognitive Function: The AREDS2 Randomized Clinical Trial. JAMA : the journal of the American Medical Association 314, 791-801, doi:10.1001/jama.2015.9677 (2015).

14           Yurko-Mauro, K. et al. Beneficial effects of docosahexaenoic acid on cognition in age-related cognitive decline. Alzheimers.Dement. 6, 456-464 (2010).

15           Cunnane, S. C., Chouinard-Watkins, R., Castellano, C. A. & Barberger-Gateau, P. Docosahexaenoic acid homeostasis, brain aging and Alzheimer's disease: Can we reconcile the evidence? Prostaglandins Leukot.Essent.Fatty Acids. (2012).

16           Cunnane, S. C. et al. Fish, docosahexaenoic acid and Alzheimer's disease. Progress in lipid research 48, 239-256, doi:10.1016/j.plipres.2009.04.001 (2009).

17           Quinn, J. F. et al. Docosahexaenoic acid supplementation and cognitive decline in Alzheimer disease: a randomized trial. JAMA. 304, 1903-1911 (2010).

18           Hennebelle, M. et al. Ageing and apoE change DHA homeostasis: relevance to age-related cognitive decline. The Proceedings of the Nutrition Society 73, 80-86, doi:10.1017/S0029665113003625 (2014).

19           Vandal, M. et al. Reduction in DHA transport to the brain of mice expressing human APOE4 compared to APOE2. Journal of neurochemistry 129, 516-526, doi:10.1111/jnc.12640 (2014).

20           Thifault, E. et al. Effects of age, sex, body mass index and APOE genotype on cardiovascular biomarker response to an n-3 polyunsaturated fatty acid supplementation. Journal of nutrigenetics and nutrigenomics 6, 73-82, doi:10.1159/000350744 (2013).

21           Mahmoudi, M. J. et al. Effect of low dose omega-3 poly unsaturated fatty acids on cognitive status among older people: a double-blind randomized placebo-controlled study. Journal of diabetes and metabolic disorders 13, 34, doi:10.1186/2251-6581-13-34 (2014).

22           Vakhapova, V. et al. Phosphatidylserine containing omega-3 Fatty acids may improve memory abilities in nondemented elderly individuals with memory complaints: results from an open-label extension study. Dementia and geriatric cognitive disorders 38, 39-45, doi:10.1159/000357793 (2014).

23           Shinto, L. et al. A randomized placebo-controlled pilot trial of omega-3 fatty acids and alpha lipoic acid in Alzheimer's disease. Journal of Alzheimer's disease : JAD 38, 111-120, doi:10.3233/JAD-130722 (2014).

24           Pardini, M. et al. Souvenaid reduces behavioral deficits and improves social cognition skills in frontotemporal dementia: a proof-of-concept study. Neuro-degenerative diseases 15, 58-62, doi:10.1159/000369811 (2015).

25           Olde Rikkert, M. G. et al. Tolerability and safety of Souvenaid in patients with mild Alzheimer's disease: results of multi-center, 24-week, open-label extension study. Journal of Alzheimer's disease : JAD 44, 471-480, doi:10.3233/JAD-141305 (2015).

26           Scheltens, P. et al. Efficacy of souvenaid in mild Alzheimer's disease: results from a randomized, controlled trial. J.Alzheimers.Dis. 31, 225-236 (2012).

27           Shah, R. C. et al. The S-Connect study: results from a randomized, controlled trial of Souvenaid in mild-to-moderate Alzheimer's disease. Alzheimer's research & therapy 5, 59, doi:10.1186/alzrt224 (2013).

28           Rangel-Huerta, O. D., Aguilera, C. M., Mesa, M. D. & Gil, A. Omega-3 long-chain polyunsaturated fatty acids supplementation on inflammatory biomakers: a systematic review of randomised clinical trials. Br.J.Nutr. 107 Suppl 2:S159-70., S159-S170 (2012).

29           Kotwal, S., Jun, M., Sullivan, D., Perkovic, V. & Neal, B. Omega 3 Fatty acids and cardiovascular outcomes: systematic review and meta-analysis. Circulation. Cardiovascular quality and outcomes 5, 808-818, doi:10.1161/CIRCOUTCOMES.112.966168 (2012).

30           Casula, M., Soranna, D., Catapano, A. L. & Corrao, G. Long-term effect of high dose omega-3 fatty acid supplementation for secondary prevention of cardiovascular outcomes: A meta-analysis of randomized, double blind, placebo controlled trials. Atherosclerosis. Supplements 14, 243-251, doi:10.1016/S1567-5688(13)70005-9 (2013).

31           Makarem, N., Chandran, U., Bandera, E. V. & Parekh, N. Dietary fat in breast cancer survival. Annual review of nutrition 33, 319-348, doi:10.1146/annurev-nutr-112912-095300 (2013).

32           Szymanski, K. M., Wheeler, D. C. & Mucci, L. A. Fish consumption and prostate cancer risk: a review and meta-analysis. The American journal of clinical nutrition 92, 1223-1233, doi:10.3945/ajcn.2010.29530 (2010).

33           Grosso, G. et al. Role of omega-3 fatty acids in the treatment of depressive disorders: a comprehensive meta-analysis of randomized clinical trials. PloS one 9, e96905, doi:10.1371/journal.pone.0096905 (2014).

34           Cole, G. M., Ma, Q. L. & Frautschy, S. A. Omega-3 fatty acids and dementia. Prostaglandins Leukot.Essent.Fatty Acids. 81, 213-221 (2009).

35           Mozaffarian, D. & Wu, J. H. (n-3) fatty acids and cardiovascular health: are effects of EPA and DHA shared or complementary? J.Nutr. 142, 614S-625S (2012).

36           Roman, G. C., Nash, D. T. & Fillit, H. Translating current knowledge into dementia prevention. Alzheimer disease and associated disorders 26, 295-299, doi:10.1097/WAD.0b013e31825cbc4b (2012).

37           Diniz, B. S., Butters, M. A., Albert, S. M., Dew, M. A. & Reynolds, C. F., 3rd. Late-life depression and risk of vascular dementia and Alzheimer's disease: systematic review and meta-analysis of community-based cohort studies. Br J Psychiatry 202, 329-335, doi:10.1192/bjp.bp.112.118307 (2013).

38           Tur, J. A., Bibiloni, M. M., Sureda, A. & Pons, A. Dietary sources of omega 3 fatty acids: public health risks and benefits. Br.J.Nutr. 107 Suppl 2:S23-52., S23-S52 (2012).

39           Villani, A. M. et al. Fish oil administration in older adults: is there potential for adverse events? A systematic review of the literature. BMC geriatrics 13, 41, doi:10.1186/1471-2318-13-41 (2013).

40           Wachira, J. K., Larson, M. K. & Harris, W. S. n-3 Fatty acids affect haemostasis but do not increase the risk of bleeding: clinical observations and mechanistic insights. The British journal of nutrition 111, 1652-1662, doi:10.1017/S000711451300425X (2014).

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