DHA and Omega-3 Fatty Acids

Docosahexaenoic acid (DHA) is a long-chain omega-3 polyunsaturated fatty acid found in fatty fish and some algae.  People may be less likely to develop Alzheimer’s disease if they eat fish twice every week or have more DHA in their blood.  However, some research does not support this idea and, in clinical trials, Alzheimer’s patients have not benefited from DHA.  DHA foods, drugs, and supplements are widely used and usually safe.

EFFICACY
Likely
with   Moderate  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 DHA more than other common omega-3 fatty acids (EPA and ALA) because the strongest evidence links DHA to brain health.

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.  Infant formula and other foods are often supplemented with DHA derived from algae.

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

Dose:  The ideal dose of DHA is not well understood but probably falls between 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 60-80 milligrams per day of DHA and 20-30 mg per day of EPA (NHANES 2009-2010).  In some studies, Americans who consume slightly more than this (180 mg/day, roughly 2-3 servings of fatty fish per week) were less likely to develop dementia [5].  Supplements of 400-2000 milligrams per day have been tested with varying but rather limited success at improving cognitive function in older people [6].

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 [7].   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].  The only vegetarian source of DHA is specific types of algae and related supplements. 
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, provided that the source does not contain toxins and does contain reliable levels of DHA and/or EPA.  Resources for the reliability of supplements are discussed in Section 9 below.

FDA-approved drugs: Doctors can prescribe pharmaceutical sources of DHA and EPA, such as Lovaza sold by GlaxoSmithKline and called Omacor outside the USA.  Other drugs are in development such as Vascepa by Amarin Pharma Inc (also called AMR101) and Epanova by Omthera Pharmaceuticals.  These compounds are reliable sources that have been rigorously tested and purified.  However, for the purposes of cognitive decline and dementia, there is no evidence yet that these drugs are more or less protective than other common sources.

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 inflammation, increase 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 [9, 10].

EPA is a shorter omega-3 fatty acid that may also improve brain function although its protective properties are less established [11].  Both EPA and DHA could also protect the brain indirectly by protecting the cardiovascular system [12] 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 [13].

Likely prevents dementia, based on moderate evidence.  People who consume relatively more DHA during their life often have improved brain health and a decreased risk of dementia as they age.  This pattern of reduced dementia risk has been observed in many but not all high-quality studies [9, 11] and it has never been tested in a clinical trial [14].  People who have a greater risk of Alzheimer’s disease because of the APOE4 genetic risk factor may be less likely to benefit from DHA [9, 11].

Possibly slows decline in people with mild cognitive impairment but unlikely to benefit people with dementia.  In clinical trials, treatment with long-chain omega-3 fatty acids has generally not helped Alzheimer’s patients.  In contrast, similar treatments have apparently helped people with mild cognitive impairment [15, 16], which is often though not always a precursor to Alzheimer’s disease and dementia.

Some scientists believe that this evidence from clinical trials suggests that Alzheimer’s must be treated as early as possible.  It’s also possible that the long-chain omega-3 fatty acids could help Alzheimer’s patients if they do not have the APOE4 genetic risk factor for Alzheimer’s disease [17] which changes the metabolic response to DHA intake [18].  More research is needed on these ideas.

In small clinical trials, the memory of patients with mild Alzheimer’s disease was improved by SouvenaidTM, a medical food available in Europe that contains DHA and EPA as well as a variety of other nutritional components [19].

There is no consistent scientific evidence that raising DHA intake can slow the rate of aging per se [6].  However, omega-3 fatty acids can sometimes reduce inflammation [20], 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 [21, 22] and some cancers [23, 24], although the evidence is inconclusive.

Very likely safe based on strong evidence.  Long-chain omega-3 fatty acids are one of the most widely consumed nutraceuticals in the Western world and they have been studied extensively for cardiovascular health.  These compounds may improve other aspects of health including cardiovascular disease, risk of death from cancer, age-related macular degeneration, Crohn’s disease, depression, and ADHD.  They are well-tolerated and generally recognized as safe at doses below 3 grams per day.  However, doses higher than 3 grams per day may cause harm [25].

• Discuss your options and choices with your health care providers.  

• Do not supplement beyond 3000 mg (3 grams) per day of DHA and EPA combined unless under medical supervision [25].  Moderate doses such as 180-2000 mg per day have more scientific evidence for both safety and possible protection from dementia.

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.  More information about planned and on-going clinical trials can be found at clinicaltrials.gov (U.S.) and at clinicaltrialsregister.eu (Europe).

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 September 2013)

VITAL study in healthy people over 65 (scheduled completion in 2016)

MAPT study in frail elders (scheduled completion in 2014)

• The Lipoic Acid and Omega-3 Fatty Acids in Alzheimer’s Disease Trial (scheduled completion in 2015)

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

• Dietary supplements are sometimes criticized for unreliable content.  To assist in finding a trusted brand, several companies independently test the quality of specific supplements:  United States Pharmacopeial Convention (USP) and ConsumerLab. The FDA also provides a useful guide to Dietary Supplements.

• Additional information on omega-3 fatty acids, including further information on dose and safety, is available from the American Journal of Clinical Nutrition, the NIH National Center for Complementary and Alternative Medicine, and the NIH Office of Dietary Supplements.  Information on foods that contain omega-3 fatty acids is available from the American Heart Association and Tufts University, although the latter site does not distinguish between sources of DHA and sources of shorter-chain omega-3 fatty acids that are less linked to brain health.

• A scientific review article written Alzheimer’s Drug Discovery Foundation Cognitive Vitality scientists [6].

1. Burdge, G.C. and P.C. Calder (2012) Conversion of alpha-linolenic acid to longer-chain polyunsaturated fatty acids in human adults. Reprod Nutr Dev 45(5): 581-597.

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

3. Loef, M. and H. Walach (2013) The omega-6/omega-3 ratio and dementia or cognitive decline: a systematic review on human studies and biological evidence. J Nutr Gerontol Geriatr 32(1): 1-23.

4. Harris, W.S., et al. (2009) 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 19(6): 902-907.

5. Schaefer, E.J., et al. (2006) Plasma phosphatidylcholine docosahexaenoic acid content and risk of dementia and Alzheimer disease: the Framingham Heart Study. Arch Neurol 63(11): 1545-1550.

6. Dacks, P.A., D.W. Shineman, and H.M. Fillit (2013) 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(3): 240-51.

7. Chung, H., et al. (2008) Frequency and type of seafood consumed influence plasma (n-3) fatty acid concentrations. J Nutr 138(12): 2422-2427.

8. Zargar, A. and M.K. Ito (2011) Long chain omega-3 dietary supplements: a review of the National Library of Medicine Herbal Supplement Database. Metab Syndr Relat Disord 9(4): 255-271.

9. Cunnane, S.C., et al. (2009) Fish, docosahexaenoic acid and Alzheimer's disease. Prog Lipid Res 48(5): 239-56.

10. Cole, G.M., Q.L. Ma, and S.A. Frautschy (2009) Omega-3 fatty acids and dementia. Prostaglandins Leukot Essent Fatty Acids 81(2-3): 213-221.

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

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

13. Roman, G.C., D.T. Nash, and H. Fillit (2012) Translating current knowledge into dementia prevention. Alzheimer Dis Assoc Disord 26(4): 295-9.

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

15. Mazereeuw, G., et al. (2012) Effects of omega-3 fatty acids on cognitive performance: a meta-analysis. Neurobiol Aging 33(7): 1482-29.

16. Lee, L.K., et al. (2013) Docosahexaenoic acid-concentrated fish oil supplementation in subjects with mild cognitive impairment (MCI): a 12-month randomised, double-blind, placebo-controlled trial. Psychopharmacology (Berl) 225(3): 605-12.

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

18. Hennebelle, M., et al. (2013) Ageing and apoE change DHA homeostasis: relevance to age-related cognitive decline. Proc Nutr Soc 2013: 1-7.

19. Scheltens, P., et al. (2012) Efficacy of souvenaid in mild Alzheimer's disease: results from a randomized, controlled trial. J Alzheimers Dis 31(1): 225-236.

20. Rangel-Huerta, O.D., et al. (2012) 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.

21. Kotwal, S., et al. (2012) Omega 3 Fatty acids and cardiovascular outcomes: systematic review and meta-analysis. Circ Cardiovasc Qual Outcomes 5(6): 808-18.

22. Casula, M., et al. (2013) 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. Atheroscler Suppl 14(2): 243-51.

23. Makarem, N., et al. (2013) Dietary fat in breast cancer survival. Annu Rev Nutr 33: 319-48.

24. Szymanski, K.M., D.C. Wheeler, and L.A. Mucci (2010) Fish consumption and prostate cancer risk: a review and meta-analysis. Am J Clin Nutr 92(5): 1223-33.

25. Tur, J.A., et al. (2012) Dietary sources of omega 3 fatty acids: public health risks and benefits. Br J Nutr 107 Suppl 2:S23-52.

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