Nutr Res Pract.  2021 Apr;15(2):137-159. 10.4162/nrp.2021.15.2.137.

Role of n-3 long-chain polyunsaturated fatty acids in human nutrition and health: review of recent studies and recommendations

• Dael PV

• KMID: 2514436
• DOI: http://doi.org/10.4162/nrp.2021.15.2.137

Abstract

Long-chain (LC) n-3 polyunsaturated fatty acids (n-3 PUFAs), in particular docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), are nutrients involved in many metabolic and physiological processes, and are referred to as n-3 LCPUFA. They have been extensively studied for their effects in human nutrition and health. This paper provides an overview on metabolism, sources, dietary intake, and status of n-3 LCPUFA. A summary of the dietary recommendations for n-3 LCPUFAs for different age groups as well as specific physiological conditions is provided. Evidence for n-3 LCPUFA in cardiovascular diseases, including new studies, is reviewed. Expert recommendations generally support a beneficial effect of n-3 LCPUFA on cardiovascular health and recommend a daily intake of 500 mg as DHA and EPA, or 1–2 servings of fish per week. The role of n-3 LCPUFA on brain health, in particular neurodegenerative disorders and depression, is reviewed. The evidence for beneficial effects of n-3 LCPUFA on neurodegenerative disorders is non-conclusive despite mechanistic support and observational data. Hence, no definite n-3 LCPUFA expert recommendations are made. Data for the beneficial effect of n-3 LCPUFA on depression are generally compelling. Expert recommendations have been established: 200–300 mg/day for depression; up to 1–2 g/day for major depressive disorder. Recent studies support a beneficial role of n-3 LCPUFAs in reducing the risk for premature birth, with a daily intake of 600–800 mg of DHA during pregnancy. Finally, international experts recently reviewed the scientific evidence on DHA and arachidonic acid (ARA) in infant nutrition and concluded that the totality of data support that infant and follow-on formulas should provide both DHA and ARA at levels similar to those in breast milk. In conclusion, the available scientific data support that dietary recommendations for n-3 LCPUFA should be established for the general population and for subjects with specific physiological conditions.

Keyword

Docosahexaenoic acid; eicosapentaenoic acid; heart; brain; adult; pregnancy; infant

Figure

• 

  Fig. 1 Metabolic pathway for n-3 LCPUFA synthesis from ALA.LCPUFA, long-chain polyunsaturated fatty acid; ALA, alpha-linolenic acid; SA, stearidonic acid; EPA, eicosapentaenoic acid; ETA, eicosatetraenoic acid; DPA, docosapentaenoic acid; DHA, docosahexaenoic acid.

Reference

1. World Health Organization (WHO). Global Status Report on Noncommunicable Diseases 2014. Geneva: WHO;2014.

2. World Health Organization (WHO). Global Action Plan for the Prevention and Control of NCDs 2013–2020 [Internet]. Geneva: WHO;2013. cited 2020 April 5. Available from: https://www.who.int/nmh/publications/ncd-action-plan/en/.

3. Mozaffarian D, Wu JH. Omega-3 fatty acids and cardiovascular disease: effects on risk factors, molecular pathways, and clinical events. J Am Coll Cardiol. 2011; 58:2047–2067. PMID: 22051327.

4. Sinn N, Milte CM, Street SJ, Buckley JD, Coates AM, Petkov J, Howe PR. Effects of n-3 fatty acids, EPA v. DHA, on depressive symptoms, quality of life, memory and executive function in older adults with mild cognitive impairment: a 6-month randomised controlled trial. Br J Nutr. 2012; 107:1682–1693. PMID: 21929835.

5. Middleton P, Gomersall JC, Gould JF, Shepherd E, Olsen SF, Makrides M. Omega-3 fatty acid addition during pregnancy. Cochrane Database Syst Rev. 2018; 11:CD003402. PMID: 30480773.

6. Lapillonne A. Enteral and parenteral lipid requirements of preterm infants. World Rev Nutr Diet. 2014; 110:82–98. PMID: 24751623.

7. Koletzko B, Bergmann K, Brenna JT, Calder PC, Campoy C, Clandinin MT, Colombo J, Daly M, Decsi T, Demmelmair H, Domellöf M, FidlerMis N, Gonzalez-Casanova I, van Goudoever JB, Hadjipanayis A, Hernell O, Lapillonne A, Mader S, Martin CR, Matthäus V, Ramakrishan U, Smuts CM, Strain SJ, Tanjung C, Tounian P, Carlson SE. Should formula for infants provide arachidonic acid along with DHA? A position paper of the European Academy of Paediatrics and the Child Health Foundation. Am J Clin Nutr. 2020; 111:10–16. PMID: 31665201.

8. Goyens PL, Spilker ME, Zock PL, Katan MB, Mensink RP. Conversion of alpha-linolenic acid in humans is influenced by the absolute amounts of alpha-linolenic acid and linoleic acid in the diet and not by their ratio. Am J Clin Nutr. 2006; 84:44–53. PMID: 16825680.

9. Kinsella JE, Lokesh B, Broughton S, Whelan J. Dietary polyunsaturated fatty acids and eicosanoids: potential effects on the modulation of inflammatory and immune cells: an overview. Nutrition. 1990; 6:24–44. PMID: 2135755.

10. Clandinin MT. Brain development and assessing the supply of polyunsaturated fatty acid. Lipids. 1999; 34:131–137. PMID: 10102239.

11. Salem N Jr, Wegher B, Mena P, Uauy R. Arachidonic and docosahexaenoic acids are biosynthesized from their 18-carbon precursors in human infants. Proc Natl Acad Sci U S A. 1996; 93:49–54. PMID: 8552667.

12. Schaeffer L, Gohlke H, Müller M, Heid IM, Palmer LJ, Kompauer I, Demmelmair H, Illig T, Koletzko B, Heinrich J. Common genetic variants of the FADS1 FADS2 gene cluster and their reconstructed haplotypes are associated with the fatty acid composition in phospholipids. Hum Mol Genet. 2006; 15:1745–1756. PMID: 16670158.

13. Micha R, Khatibzadeh S, Shi P, Fahimi S, Lim S, Andrews KG, Engell RE, Powles J, Ezzati M, Mozaffarian D. Global Burden of Diseases Nutrition and Chronic Diseases Expert Group NutriCoDE. Global, regional, and national consumption levels of dietary fats and oils in 1990 and 2010: a systematic analysis including 266 country-specific nutrition surveys. BMJ. 2014; 348:g2272. PMID: 24736206.

14. Patterson AC, Hogg RC, Kishi DM, Stark KD. Biomarker and dietary validation of a Canadian food frequency questionnaire to measure eicosapentaenoic and docosahexaenoic acid intakes from whole food, functional food, and nutraceutical sources. J Acad Nutr Diet. 2012; 112:1005–1014. PMID: 22583924.

15. Fratesi JA, Hogg RC, Young-Newton GS, Patterson AC, Charkhzarin P, Block Thomas K, Sharratt MT, Stark KD. Direct quantitation of omega-3 fatty acid intake of Canadian residents of a long-term care facility. Appl Physiol Nutr Metab. 2009; 34:1–9. PMID: 19234579.

16. Patterson AC, Metherel AH, Hanning RM, Stark KD. The percentage of DHA in erythrocytes can detect non-adherence to advice to increase EPA and DHA intakes. Br J Nutr. 2014; 111:270–278. PMID: 23920312.

17. Block RC, Harris WS, Pottala JV. Determinants of blood cell omega-3 fatty acid content. Open Biomark J. 2008; 1:1–6. PMID: 19953197.

18. Flock MR, Skulas-Ray AC, Harris WS, Etherton TD, Fleming JA, Kris-Etherton PM. Determinants of erythrocyte omega-3 fatty acid content in response to fish oil supplementation: a dose-response randomized controlled trial. J Am Heart Assoc. 2013; 2:e000513. PMID: 24252845.

19. Stark KD, Beblo S, Murthy M, Whitty JE, Buda-Abela M, Janisse J, Rockett H, Martier SS, Sokol RJ, Hannigan JH, Salem N Jr. Alcohol consumption in pregnant, black women is associated with decreased plasma and erythrocyte docosahexaenoic acid. Alcohol Clin Exp Res. 2005; 29:130–140. PMID: 15654301.

20. Harris WS, Pottala JV, Lacey SM, Vasan RS, Larson MG, Robins SJ. Clinical correlates and heritability of erythrocyte eicosapentaenoic and docosahexaenoic acid content in the Framingham Heart Study. Atherosclerosis. 2012; 225:425–431. PMID: 22727409.

21. Crowe FL, Skeaff CM, Green TJ, Gray AR. Serum n-3 long-chain PUFA differ by sex and age in a population-based survey of New Zealand adolescents and adults. Br J Nutr. 2008; 99:168–174. PMID: 17678566.

22. Siscovick DS, Raghunathan TE, King I, Weinmann S, Wicklund KG, Albright J, Bovbjerg V, Arbogast P, Smith H, Kushi LH, Cobb LA, Copass MK, Psaty BM, Lemaitre R, Retzlaff B, Childs M, Knopp RH. Dietary intake and cell membrane levels of long-chain n-3 polyunsaturated fatty acids and the risk of primary cardiac arrest. JAMA. 1995; 274:1363–1367. PMID: 7563561.

23. Albert CM, Campos H, Stampfer MJ, Ridker PM, Manson JE, Willett WC, Ma J. Blood levels of long-chain n-3 fatty acids and the risk of sudden death. N Engl J Med. 2002; 346:1113–1118. PMID: 11948270.

24. Schaefer EJ, Bongard V, Beiser AS, Lamon-Fava S, Robins SJ, Au R, Tucker KL, Kyle DJ, Wilson PW, Wolf PA. Plasma phosphatidylcholine docosahexaenoic acid content and risk of dementia and Alzheimer disease: the Framingham Heart Study. Arch Neurol. 2006; 63:1545–1550. PMID: 17101822.

25. Stark KD, Van Elswyk ME, Higgins MR, Weatherford CA, Salem N Jr. Global survey of the omega-3 fatty acids, docosahexaenoic acid and eicosapentaenoic acid in the blood stream of healthy adults. Prog Lipid Res. 2016; 63:132–152. PMID: 27216485.

26. Food and Agriculture Organization of the United Nations. FAO Fats and Fatty Acids in Human Nutrition. Report of an Expert Consultation. Rome: Food and Agriculture Organization of the United Nations;2010.

27. EFSA Panel on Dietetic Products, Nutrition, and Allergies (NDA). Scientific Opinion on Dietary Reference Values for fats, including saturated fatty acids, polyunsaturated fatty acids, monounsaturated fatty acids, trans fatty acids, and cholesterol. EFSA J. 2010; 8:1461.

28. EFSA Panel on Dietetic Products, Nutrition and Allergies (NDA). Scientific Opinion on the Tolerable Upper Intake Level of eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA) and docosapentaenoic acid (DPA). EFSA J. 2012; 10:2815.

29. Institute of Medicine (US). Dietary Reference Intakes for Energy, Carbohydrate, Fiber, Fat, Fatty Acids, Cholesterol, Protein, and Amino Acids. Washington, D.C.: National Academy Press;2005.

30. U.S. Food and Drug Administration (FDA). Advice about Eating Fish [Internet]. Silver Spring: FDA;2020. cited 2020 April 5. Available from: https://www.fda.gov/food/consumers/advice-about-eating-fish.

31. U.S. Food and Drug Administration (FDA). Qualified Health Claims: Letters of Enforcement Discretion [Internet]. Silver Spring: FDA;2020. cited 2020 April 5. Available from: https://www.fda.gov/food/food-labeling-nutrition/qualified-health-claims-letters-enforcement-discretion.

32. U.S. Department of Health and Human Services. U.S. Department of Agriculture. 2015–2020 Dietary Guidelines for Americans. 8th ed. Washington, D.C: U.S. Government Printing Office;2015.

33. US Department of Agriculture. US Department of Health and Human Services. Scientific Report of the 2015 Dietary Guidelines Advisory Committee. Washington, D.C.: U.S. Government Printing Office;2015.

34. National Health and Medical Research Council (AU). Nutrient Reference Values for Australia and New Zealand including Recommended Dietary Intakes (version 1.2). Canberra: National Health and Medical Research Council (AU);2017.

35. Dolecek TA. Epidemiological evidence of relationships between dietary polyunsaturated fatty acids and mortality in the multiple risk factor intervention trial. Proc Soc Exp Biol Med. 1992; 200:177–182. PMID: 1579579.

36. Iso H, Rexrode KM, Stampfer MJ, Manson JE, Colditz GA, Speizer FE, Hennekens CH, Willett WC. Intake of fish and omega-3 fatty acids and risk of stroke in women. JAMA. 2001; 285:304–312. PMID: 11176840.

37. Department of Health and Human Services, U.S. Food and Drug Administration. Substances affirmed as generally recognized as safe: menhaden oil [Internet]. College Park: Office of the Federal Register;2005. cited 2020 April 5. https://www.federalregister.gov/documents/2005/03/23/05-5641/substances-affirmed-as-generally-recognized-as-safe-menhaden-oil.

38. French Agency for Food, Environmental and Occupational Health Safety (ANSES). Update of the Recommended Nutritional Intake for Fatty Acids. Collective Expert Report [Internet]. Maisons-Alfort: ANSES;2011. cited 2020 April 5. Available from: https://www.anses.fr/en/system/files/NUT2006sa0359Ra.pdf.

39. Beaufrère B, Bresson JL, Briend A, Ghisolfi J, Goulet A, Putet G, Rieu D, Turck D, Vidailhet M. Martin A, editor. Recommended Nutritional Intakes for the French Population. Paris: Ed Tec et Doc.;2001.

40. Mozaffarian D, Wu JH. (n-3) fatty acids and cardiovascular health: are effects of EPA and DHA shared or complementary? J Nutr. 2012; 142:614S–625S. PMID: 22279134.

41. Kris-Etherton PM, Harris WS, Appel LJ; Nutrition Committee. Fish consumption, fish oil, omega-3 fatty acids, and cardiovascular disease. Circulation. 2002; 106:2747–2757. PMID: 12438303.

42. Siscovick DS, Barringer TA, Fretts AM, Wu JH, Lichtenstein AH, Costello RB, Kris-Etherton PM, Jacobson TA, Engler MB, Alger HM, Appel LJ, Mozaffarian D. American Heart Association Nutrition Committee of the Council on Lifestyle and Cardiometabolic Health. Council on Epidemiology and Prevention. Council on Cardiovascular Disease in the Young. Council on Cardiovascular and Stroke Nursing. Council on Clinical Cardiology. Omega-3 polyunsaturated fatty acid (fish oil) supplementation and the prevention of clinical cardiovascular disease: a science advisory from the American Heart Association. Circulation. 2017; 135:e867–e884. PMID: 28289069.

43. Skulas-Ray AC, Wilson PWF, Harris WS, Brinton EA, Kris-Etherton PM, Richter CK, Jacobson TA, Engler MB, Miller M, Robinson JG, Blum CB, Rodriguez-Leyva D, de Ferranti SD, Welty FK. American Heart Association Council on Arteriosclerosis, Thrombosis and Vascular Biology. Council on Lifestyle and Cardiometabolic Health. Cardiovascular Disease in the Young. Council on Cardiovascular and Stroke Nursing. Council on Clinical Cardiology. Omega-3 fatty acids for the management of hypertriglyceridemia: a science advisory from the American Heart Association. Circulation. 2019; 140:e673–91. PMID: 31422671.

44. Aung T, Halsey J, Kromhout D, Gerstein HC, Marchioli R, Tavazzi L, Geleijnse JM, Rauch B, Ness A, Galan P, Chew EY, Bosch J, Collins R, Lewington S, Armitage J, Clarke R. Omega-3 Treatment Trialists' Collaboration. Associations of omega-3 fatty acid supplement use with cardiovascular disease risks: meta-analysis of 10 trials involving 77,917 individuals. JAMA Cardiol. 2018; 3:225–234. PMID: 29387889.

45. Abdelhamid AS, Brown TJ, Brainard JS, Biswas P, Thorpe GC, Moore HJ, Deane KH, AlAbdulghafoor FK, Summerbell CD, Worthington HV, Song F, Hooper L. Omega-3 fatty acids for the primary and secondary prevention of cardiovascular disease. Cochrane Database Syst Rev. 2018; 7:CD003177. PMID: 30019766.

46. Arca M, Borghi C, Pontremoli R, De Ferrari GM, Colivicchi F, Desideri G, Temporelli PL. Hypertriglyceridemia and omega-3 fatty acids: Their often overlooked role in cardiovascular disease prevention. Nutr Metab Cardiovasc Dis. 2018; 28:197–205. PMID: 29397253.

47. Rimm EB, Appel LJ, Chiuve SE, Djoussé L, Engler MB, Kris-Etherton PM, Mozaffarian D, Siscovick DS, Lichtenstein AH. American Heart Association Nutrition Committee of the Council on Lifestyle and Cardiometabolic Health. Council on Epidemiology and Prevention. Council on Cardiovascular Disease in the Young. Council on Cardiovascular and Stroke Nursing. Council on Clinical Cardiology. Seafood long-chain n-3 polyunsaturated fatty acids and cardiovascular disease: a science advisory from the American Heart Association. Circulation. 2018; 138:e35–47. PMID: 29773586.

48. Pizzini A, Lunger L, Sonnweber T, Weiss G, Tancevski I. The role of omega-3 fatty acids in the setting of coronary artery disease and COPD: a review. Nutrients. 2018; 10:1864.

49. Wen YT, Dai JH, Gao Q. Effects of omega-3 fatty acid on major cardiovascular events and mortality in patients with coronary heart disease: a meta-analysis of randomized controlled trials. Nutr Metab Cardiovasc Dis. 2014; 24:470–475. PMID: 24472636.

50. Kwak SM, Myung SK, Lee YJ, Seo HG. Korean Meta-analysis Study Group. Efficacy of omega-3 fatty acid supplements (eicosapentaenoic acid and docosahexaenoic acid) in the secondary prevention of cardiovascular disease: a meta-analysis of randomized, double-blind, placebo-controlled trials. Arch Intern Med. 2012; 172:686–694. PMID: 22493407.

51. Nestel P, Clifton P, Colquhoun D, Noakes M, Mori TA, Sullivan D, Thomas B. Indications for omega-3 long chain polyunsaturated fatty acid in the prevention and treatment of cardiovascular disease. Heart Lung Circ. 2015; 24:769–779. PMID: 25936871.

52. Meyer BJ, Groot RH. Effects of omega-3 long chain polyunsaturated fatty acid supplementation on cardiovascular mortality: the importance of the dose of DHA. Nutrients. 2017; 9:1305.

53. Manson JE, Cook NR, Lee IM, Christen W, Bassuk SS, Mora S, Gibson H, Albert CM, Gordon D, Copeland T, D'Agostino D, Friedenberg G, Ridge C, Bubes V, Giovannucci EL, Willett WC, Buring JE. VITAL Research Group. Marine n−3 fatty acids and prevention of cardiovascular disease and cancer. N Engl J Med. 2019; 380:23–32. PMID: 30415637.

54. Bhatt DL, Steg PG, Miller M, Brinton EA, Jacobson TA, Ketchum SB, Doyle RT Jr, Juliano RA, Jiao L, Granowitz C, Tardif JC, Ballantyne CM. REDUCE-IT Investigators. Cardiovascular risk reduction with icosapent ethyl for hypertriglyceridemia. N Engl J Med. 2019; 380:11–22. PMID: 30415628.

55. Uauy R, Hoffman DR, Peirano P, Birch DG, Birch EE. Essential fatty acids in visual and brain development. Lipids. 2001; 36:885–895. PMID: 11724460.

56. Uauy R, Mena P, Rojas C. Essential fatty acids in early life: structural and functional role. Proc Nutr Soc. 2000; 59:3–15. PMID: 10828169.

57. Carlson SE, Colombo J. Docosahexaenoic acid and arachidonic acid nutrition in early development. Adv Pediatr. 2016; 63:453–471. PMID: 27426911.

58. Makrides M, Gibson RA. Long-chain polyunsaturated fatty acid requirements during pregnancy and lactation. Am J Clin Nutr. 2000; 71:307S–311S. PMID: 10617987.

59. Sattar N, Berry C, Greer IA. Essential fatty acids in relation to pregnancy complications and fetal development. Br J Obstet Gynaecol. 1998; 105:1248–1255. PMID: 9883915.

60. Cansev M, Wurtman RJ, Sakamoto T, Ulus IH. Oral administration of circulating precursors for membrane phosphatides can promote the synthesis of new brain synapses. Alzheimers Dement. 2008; 4:S153–68. PMID: 18631994.

61. Beltz BS, Tlusty MF, Benton JL, Sandeman DC. Omega-3 fatty acids upregulate adult neurogenesis. Neurosci Lett. 2007; 415:154–158. PMID: 17240063.

62. Kawakita E, Hashimoto M, Shido O. Docosahexaenoic acid promotes neurogenesis in vitro and in vivo . Neuroscience. 2006; 139:991–997. PMID: 16527422.

63. Cutuli D. Functional and structural benefits induced by omega-3 polyunsaturated fatty acids during aging. Curr Neuropharmacol. 2017; 15:534–542. PMID: 27306037.

64. Aryal S, Hussain S, Drevon CA, Nagelhus E, Hvalby Ø, Jensen V, Walaas SI, Davanger S. Omega-3 fatty acids regulate plasticity in distinct hippocampal glutamatergic synapses. Eur J Neurosci. 2019; 49:40–50. PMID: 30367533.

65. Castro-Gómez P, Garcia-Serrano A, Visioli F, Fontecha J. Relevance of dietary glycerophospholipids and sphingolipids to human health. Prostaglandins Leukot Essent Fatty Acids. 2015; 101:41–51. PMID: 26242691.

66. Cardoso C, Afonso C, Bandarra NM. Dietary DHA and health: cognitive function ageing. Nutr Res Rev. 2016; 29:281–294. PMID: 27866493.

67. Calviello G, Su HM, Weylandt KH, Fasano E, Serini S, Cittadini A. Experimental evidence of ω-3 polyunsaturated fatty acid modulation of inflammatory cytokines and bioactive lipid mediators: their potential role in inflammatory, neurodegenerative, and neoplastic diseases. Biomed Res Int. 2013; 2013:743171. PMID: 23691510.

68. Moore K, Hughes CF, Ward M, Hoey L, McNulty H. Diet, nutrition and the ageing brain: current evidence and new directions. Proc Nutr Soc. 2018; 77:152–163. PMID: 29316987.

69. Yassine HN, Braskie MN, Mack WJ, Castor KJ, Fonteh AN, Schneider LS, Harrington MG, Chui HC. Association of docosahexaenoic acid supplementation with Alzheimer disease stage in apolipoprotein E ε4 carriers: a review. JAMA Neurol. 2017; 74:339–347. PMID: 28114437.

70. Butler M, Nelson VA, Davila H, Ratner E, Fink HA, Hemmy LS, McCarten JR, Barclay TR, Brasure M, Kane RL. Over-the-counter supplement interventions to prevent cognitive decline, mild cognitive impairment, and clinical Alzheimer-type dementia: a systematic review. Ann Intern Med. 2018; 168:52–62. PMID: 29255909.

71. Burckhardt M, Herke M, Wustmann T, Watzke S, Langer G, Fink A. Omega-3 fatty acids for the treatment of dementia. Cochrane Database Syst Rev. 2016; 4:CD009002. PMID: 27063583.

72. Dangour AD, Whitehouse PJ, Rafferty K, Mitchell SA, Smith L, Hawkesworth S, Vellas B. B-vitamins and fatty acids in the prevention and treatment of Alzheimer's disease and dementia: a systematic review. J Alzheimers Dis. 2010; 22:205–224. PMID: 20847412.

73. Sydenham E, Dangour AD, Lim WS. Omega 3 fatty acid for the prevention of cognitive decline and dementia. Cochrane Database Syst Rev. 2012; 6:CD005379.

74. Chew EY, Clemons TE, Agrón E, Launer LJ, Grodstein F, Bernstein PS. Age-Related Eye Disease Study 2 (AREDS2) Research Group. Effect of omega-3 fatty acids, lutein/zeaxanthin, or other nutrient supplementation on cognitive function: the AREDS2 randomized clinical trial. JAMA. 2015; 314:791–801. PMID: 26305649.

75. Tully AM, Roche HM, Doyle R, Fallon C, Bruce I, Lawlor B, Coakley D, Gibney MJ. Low serum cholesteryl ester-docosahexaenoic acid levels in Alzheimer's disease: a case-control study. Br J Nutr. 2003; 89:483–489. PMID: 12654166.

76. Yassine HN, Feng Q, Azizkhanian I, Rawat V, Castor K, Fonteh AN, Harrington MG, Zheng L, Reed BR, DeCarli C, Jagust WJ, Chui HC. Association of serum docosahexaenoic acid with cerebral amyloidosis. JAMA Neurol. 2016; 73:1208–1216. PMID: 27532692.

77. van Gelder BM, Tijhuis M, Kalmijn S, Kromhout D. Fish consumption, n-3 fatty acids, and subsequent 5-y cognitive decline in elderly men: the Zutphen Elderly Study. Am J Clin Nutr. 2007; 85:1142–1147. PMID: 17413117.

78. Kalmijn S, Launer LJ, Ott A, Witteman JC, Hofman A, Breteler MM. Dietary fat intake and the risk of incident dementia in the Rotterdam Study. Ann Neurol. 1997; 42:776–782. PMID: 9392577.

79. Engelhart MJ, Geerlings MI, Ruitenberg A, Van Swieten JC, Hofman A, Witteman JC, Breteler MM. Diet and risk of dementia: Does fat matter?: the Rotterdam Study. Neurology. 2002; 59:1915–1921. PMID: 12499483.

80. Pottala JV, Yaffe K, Robinson JG, Espeland MA, Wallace R, Harris WS. Higher RBC EPA + DHA corresponds with larger total brain and hippocampal volumes: WHIMS-MRI study. Neurology. 2014; 82:435–442. PMID: 24453077.

81. Tan ZS, Harris WS, Beiser AS, Au R, Himali JJ, Debette S, Pikula A, Decarli C, Wolf PA, Vasan RS, Robins SJ, Seshadri S. Red blood cell ω-3 fatty acid levels and markers of accelerated brain aging. Neurology. 2012; 78:658–664. PMID: 22371413.

82. Zhang Y, Chen J, Qiu J, Li Y, Wang J, Jiao J. Intakes of fish and polyunsaturated fatty acids and mild-to-severe cognitive impairment risks: a dose-response meta-analysis of 21 cohort studies. Am J Clin Nutr. 2016; 103:330–340. PMID: 26718417.

83. Dangour AD, Allen E, Elbourne D, Fasey N, Fletcher AE, Hardy P, Holder GE, Knight R, Letley L, Richards M, Uauy R. 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; 91:1725–1732. PMID: 20410089.

84. Quinn JF, Raman R, Thomas RG, Yurko-Mauro K, Nelson EB, Van Dyck C, Galvin JE, Emond J, Jack CR Jr, Weiner M, Shinto L, Aisen PS. Docosahexaenoic acid supplementation and cognitive decline in Alzheimer disease: a randomized trial. JAMA. 2010; 304:1903–1911. PMID: 21045096.

85. Freund-Levi Y, Eriksdotter-Jönhagen M, Cederholm T, Basun H, Faxén-Irving G, Garlind A, Vedin I, Vessby B, Wahlund LO, Palmblad J. Omega-3 fatty acid treatment in 174 patients with mild to moderate Alzheimer disease: OmegAD study: a randomized double-blind trial. Arch Neurol. 2006; 63:1402–1408. PMID: 17030655.

86. 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; 225:605–612. PMID: 22932777.

87. Jiao J, Li Q, Chu J, Zeng W, Yang M, Zhu S. Effect of n-3 PUFA supplementation on cognitive function throughout the life span from infancy to old age: a systematic review and meta-analysis of randomized controlled trials. Am J Clin Nutr. 2014; 100:1422–1436. PMID: 25411277.

88. Yurko-Mauro K, Alexander DD, Van Elswyk ME. Docosahexaenoic acid and adult memory: a systematic review and meta-analysis. PLoS One. 2015; 10:e0120391. PMID: 25786262.

89. Mazereeuw G, Lanctôt KL, Chau SA, Swardfager W, Herrmann N. Effects of ω-3 fatty acids on cognitive performance: a meta-analysis. Neurobiol Aging. 2012; 33:1482.e17–1482.e29.

90. Avallone R, Vitale G, Bertolotti M. Omega-3 fatty acids and neurodegenerative diseases: new evidence in clinical trials. Int J Mol Sci. 2019; 20:4256.

91. Belmaker RH, Agam G. Major depressive disorder. N Engl J Med. 2008; 358:55–68. PMID: 18172175.

92. Murray CJ, Lopez AD. Global mortality, disability, and the contribution of risk factors: Global Burden of Disease Study. Lancet. 1997; 349:1436–1442. PMID: 9164317.

93. Cipriani A, Furukawa TA, Salanti G, Chaimani A, Atkinson LZ, Ogawa Y, Leucht S, Ruhe HG, Turner EH, Higgins JP, Egger M, Takeshima N, Hayasaka Y, Imai H, Shinohara K, Tajika A, Ioannidis JP, Geddes JR. Comparative efficacy and acceptability of 21 antidepressant drugs for the acute treatment of adults with major depressive disorder: a systematic review and network meta-analysis. Lancet. 2018; 391:1357–1366. PMID: 29477251.

94. Hibbeln JR, Nieminen LR, Blasbalg TL, Riggs JA, Lands WE. Healthy intakes of n-3 and n-6 fatty acids: estimations considering worldwide diversity. Am J Clin Nutr. 2006; 83:1483S–1493S. PMID: 16841858.

95. Connor WE. Importance of n-3 fatty acids in health and disease. Am J Clin Nutr. 2000; 71:171S–175S. PMID: 10617967.

96. Su KP. Biological mechanism of antidepressant effect of omega-3 fatty acids: how does fish oil act as a ‘mind-body interface’? Neurosignals. 2009; 17:144–152. PMID: 19190401.

97. Su KP, Shen WW, Huang SY. Effects of polyunsaturated fatty acids on psychiatric disorders. Am J Clin Nutr. 2000; 72:1241. PMID: 11063464.

98. Lin PY, Huang SY, Su KP. A meta-analytic review of polyunsaturated fatty acid compositions in patients with depression. Biol Psychiatry. 2010; 68:140–147. PMID: 20452573.

99. Hibbeln JR. Fish consumption and major depression. Lancet. 1998; 351:1213.

100. Nemets B, Stahl Z, Belmaker RH. Addition of omega-3 fatty acid to maintenance medication treatment for recurrent unipolar depressive disorder. Am J Psychiatry. 2002; 159:477–479. PMID: 11870016.

101. Peet M, Horrobin DF. A dose-ranging study of the effects of ethyl-eicosapentaenoate in patients with ongoing depression despite apparently adequate treatment with standard drugs. Arch Gen Psychiatry. 2002; 59:913–919. PMID: 12365878.

102. Su KP, Huang SY, Chiu CC, Shen WW. Omega-3 fatty acids in major depressive disorder. A preliminary double-blind, placebo-controlled trial. Eur Neuropsychopharmacol. 2003; 13:267–271. PMID: 12888186.

103. Jazayeri S, Tehrani-Doost M, Keshavarz SA, Hosseini M, Djazayery A, Amini H, Jalali M, Peet M. Comparison of therapeutic effects of omega-3 fatty acid eicosapentaenoic acid and fluoxetine, separately and in combination, in major depressive disorder. Aust N Z J Psychiatry. 2008; 42:192–198. PMID: 18247193.

104. Su KP, Huang SY, Chiu TH, Huang KC, Huang CL, Chang HC, Pariante CM. Omega-3 fatty acids for major depressive disorder during pregnancy: results from a randomized, double-blind, placebo-controlled trial. J Clin Psychiatry. 2008; 69:644–651. PMID: 18370571.

105. Frangou S, Lewis M, McCrone P. Efficacy of ethyl-eicosapentaenoic acid in bipolar depression: randomised double-blind placebo-controlled study. Br J Psychiatry. 2006; 188:46–50. PMID: 16388069.

106. da Silva TM, Munhoz RP, Alvarez C, Naliwaiko K, Kiss A, Andreatini R, Ferraz AC. Depression in Parkinson's disease: a double-blind, randomized, placebo-controlled pilot study of omega-3 fatty-acid supplementation. J Affect Disord. 2008; 111:351–359. PMID: 18485485.

107. Mischoulon D, Papakostas GI, Dording CM, Farabaugh AH, Sonawalla SB, Agoston AM, Smith J, Beaumont EC, Dahan LE, Alpert JE, Nierenberg AA, Fava M. A double-blind, randomized controlled trial of ethyl-eicosapentaenoate for major depressive disorder. J Clin Psychiatry. 2009; 70:1636–1644. PMID: 19709502.

108. Rapaport MH, Nierenberg AA, Schettler PJ, Kinkead B, Cardoos A, Walker R, Mischoulon D. Inflammation as a predictive biomarker for response to omega-3 fatty acids in major depressive disorder: a proof-of-concept study. Mol Psychiatry. 2016; 21:71–79. PMID: 25802980.

109. Lespérance F, Frasure-Smith N, St-André E, Turecki G, Lespérance P, Wisniewski SR. The efficacy of omega-3 supplementation for major depression: a randomized controlled trial. J Clin Psychiatry. 2011; 72:1054–1062. PMID: 20584525.

110. Gertsik L, Poland RE, Bresee C, Rapaport MH. Omega-3 fatty acid augmentation of citalopram treatment for patients with major depressive disorder. J Clin Psychopharmacol. 2012; 32:61–64. PMID: 22198441.

111. Martins JG. EPA but not DHA appears to be responsible for the efficacy of omega-3 long chain polyunsaturated fatty acid supplementation in depression: evidence from a meta-analysis of randomized controlled trials. J Am Coll Nutr. 2009; 28:525–542. PMID: 20439549.

112. Bloch MH, Hannestad J. Omega-3 fatty acids for the treatment of depression: systematic review and meta-analysis. Mol Psychiatry. 2012; 17:1272–1282. PMID: 21931319.

113. Martins JG, Bentsen H, Puri BK. Eicosapentaenoic acid appears to be the key omega-3 fatty acid component associated with efficacy in major depressive disorder: a critique of Bloch and Hannestad and updated meta-analysis. Mol Psychiatry. 2012; 17:1144–1149. PMID: 22488258.

114. Grosso G, Pajak A, Marventano S, Castellano S, Galvano F, Bucolo C, Drago F, Caraci F. Role of omega-3 fatty acids in the treatment of depressive disorders: a comprehensive meta-analysis of randomized clinical trials. PLoS One. 2014; 9:e96905. PMID: 24805797.

115. Mocking RJ, Harmsen I, Assies J, Koeter MW, Ruhé HG, Schene AH. Meta-analysis and meta-regression of omega-3 polyunsaturated fatty acid supplementation for major depressive disorder. Transl Psychiatry. 2016; 6:e756. PMID: 26978738.

116. Bai ZG, Bo A, Wu SJ, Gai QY, Chi I. Omega-3 polyunsaturated fatty acids and reduction of depressive symptoms in older adults: a systematic review and meta-analysis. J Affect Disord. 2018; 241:241–248. PMID: 30138808.

117. Hallahan B, Ryan T, Hibbeln JR, Murray IT, Glynn S, Ramsden CE, SanGiovanni JP, Davis JM. Efficacy of omega-3 highly unsaturated fatty acids in the treatment of depression. Br J Psychiatry. 2016; 209:192–201. PMID: 27103682.

118. Lin PY, Su KP. A meta-analytic review of double-blind, placebo-controlled trials of antidepressant efficacy of omega-3 fatty acids. J Clin Psychiatry. 2007; 68:1056–1061. PMID: 17685742.

119. Lin PY, Mischoulon D, Freeman MP, Matsuoka Y, Hibbeln J, Belmaker RH, Su KP. Are omega-3 fatty acids antidepressants or just mood-improving agents? The effect depends upon diagnosis, supplement preparation, and severity of depression. Mol Psychiatry. 2012; 17:1161–1163. PMID: 22824812.

120. Appleton KM, Sallis HM, Perry R, Ness AR, Churchill R. Omega-3 fatty acids for depression in adults. Cochrane Database Syst Rev. 2015; 2015:CD004692.

121. Su KP, Wang SM, Pae CU. Omega-3 polyunsaturated fatty acids for major depressive disorder. Expert Opin Investig Drugs. 2013; 22:1519–1534.

122. Su KP. Personalized medicine with Omega-3 fatty acids for depression in children and pregnant women and depression associated with inflammation. J Clin Psychiatry. 2015; 76:e1476–7. PMID: 26646045.

123. Chang CH, Tseng PT, Chen NY, Lin PC, Lin PY, Chang JP, Kuo FY, Lin J, Wu MC, Su KP. Safety and tolerability of prescription omega-3 fatty acids: a systematic review and meta-analysis of randomized controlled trials. Prostaglandins Leukot Essent Fatty Acids. 2018; 129:1–12. PMID: 29482765.

124. Su KP. Nutrition, psychoneuroimmunology and depression: the therapeutic implications of omega-3 fatty acids in interferon-α-induced depression. Biomedicine (Taipei). 2015; 5:21. PMID: 26615538.

125. Song C, Shieh CH, Wu YS, Kalueff A, Gaikwad S, Su KP. The role of omega-3 polyunsaturated fatty acids eicosapentaenoic and docosahexaenoic acids in the treatment of major depression and Alzheimer's disease: acting separately or synergistically? Prog Lipid Res. 2016; 62:41–54. PMID: 26763196.

126. Li F, Liu X, Zhang D. Fish consumption and risk of depression: a meta-analysis. J Epidemiol Community Health. 2016; 70:299–304. PMID: 26359502.

127. Liao Y, Xie B, Zhang H, He Q, Guo L, Subramaniapillai M, Fan B, Lu C, Mclntyer RS. Efficacy of omega-3 PUFAs in depression: a meta-analysis. Transl Psychiatry. 2019; 9:190. PMID: 31383846.

128. Guu TW, Mischoulon D, Sarris J, Hibbeln J, McNamara RK, Hamazaki K, Freeman MP, Maes M, Matsuoka YJ, Belmaker RH, Jacka F, Pariante C, Berk M, Marx W, Su KP. International Society for Nutritional Psychiatry Research Practice Guidelines for omega-3 fatty acids in the treatment of major depressive disorder. Psychother Psychosom. 2019; 88:263–273. PMID: 31480057.

129. Larqué E, Gil-Sánchez A, Prieto-Sánchez MT, Koletzko B. Omega 3 fatty acids, gestation and pregnancy outcomes. Br J Nutr. 2012; 107(Suppl 2):S77–S84. PMID: 22591905.

130. Makrides M, Gibson RA, McPhee AJ, Yelland L, Quinlivan J, Ryan P, DOMInO Investigative Team . Effect of DHA supplementation during pregnancy on maternal depression and neurodevelopment of young children: a randomized controlled trial. JAMA. 2010; 304:1675–1683. PMID: 20959577.

131. Carlson SE, Colombo J, Gajewski BJ, Gustafson KM, Mundy D, Yeast J, Georgieff MK, Markley LA, Kerling EH, Shaddy DJ. DHA supplementation and pregnancy outcomes. Am J Clin Nutr. 2013; 97:808–815. PMID: 23426033.

132. Shireman TI, Kerling EH, Gajewski BJ, Colombo J, Carlson SE. Docosahexaenoic acid supplementation (DHA) and the return on investment for pregnancy outcomes. Prostaglandins Leukot Essent Fatty Acids. 2016; 111:8–10. PMID: 27499448.

133. de Seymour JV, Simmonds LA, Gould J, Makrides M, Middleton P. Omega-3 fatty acids to prevent preterm birth: Australian pregnant women's preterm birth awareness and intentions to increase omega-3 fatty acid intake. Nutr J. 2019; 18:74. PMID: 31727060.

134. Koletzko B, Poindexter B, Uauy R. Recommended nutrient intake levels for stable, fully enterally fed very low birth weight infants. World Rev Nutr Diet. 2014; 110:297–299. PMID: 24751638.