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Current evidence for the clinical use of long-chain polyunsaturated N-3 fatty acids to prevent age-related cognitive decline and Alzheimer’s disease

Abstract

An NIH State of the Science Conference panel concluded in 2010 that insufficient evidence is available to recommend the use of any primary prevention therapy for Alzheimer’s disease or cognitive decline with age. Despite the insufficient evidence, candidate therapies with varying levels of evidence for safety and efficacy are taken by the public and discussed in the media. One example is the long-chain n-3 (omega-3) polyunsaturated fatty acids (n-3 LC-PUFA), DHA and EPA, found in some fish and dietary supplements. With this report, we seek to provide a practical overview and rating of the level and type of available evidence that n-3 LC-PUFA supplements are safe and protective against cognitive aging and Alzheimer’s disease, with additional discussion of the evidence for effects on quality of life, vascular aging, and the rate of aging. We discuss available sources, dose, bioavailability, and variables that may impact the response to n-3 LC-PUFA treatment such as baseline n-3 LC-PUFA status, APOE ɛ4 genotype, depression, and background diet. Lastly, we list ongoing clinical trials and propose next research steps to validate these fatty acids for primary prevention of cognitive aging and dementia. Of particular relevance, epidemiology indicates a higher risk of cognitive decline in people in the lower quartile of n-3 LC-PUFA intake or blood levels but these populations have not been specifically targeted by RCTs.

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References

  1. Alzheimer’s Association 2010 Changing the Trajectory of Alzheimer’s Disease: A National Imperative. http://www.alz.org/trajectory.

  2. Daviglus ML, Bell CC, Berrettini W, Bowen PE, Connolly ES, Jr., Cox NJ, Dunbar-Jacob JM, Granieri EC, Hunt G, McGarry K, Patel D, Potosky AL, Sanders-Bush E, Silberberg D, Trevisan M 2010 National Institutes of Health State-of-the-Science Conference statement: preventing alzheimer disease and cognitive decline. NIH Consens State Sci Statements 27:1–30

    PubMed  Google Scholar 

  3. Muldoon MF, Ryan CM, Sheu L, Yao JK, Conklin SM, Manuck SB 2010 Serum phospholipid docosahexaenonic acid is associated with cognitive functioning during middle adulthood. J Nutr 140:848–853

    PubMed  CAS  Article  Google Scholar 

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

    PubMed  Article  Google Scholar 

  5. Huang TL 2010 Omega-3 fatty acids, cognitive decline, and Alzheimer’s disease: a critical review and evaluation of the literature. J Alzheimers Dis 21:673–690

    PubMed  CAS  Google Scholar 

  6. Samieri C, Maillard P, Crivello F, Proust-Lima C, Peuchant E, Helmer C, Amieva H, Allard M, Dartigues JF, Cunnane SC, Mazoyer BM, Barberger-Gateau P 2012 Plasma long-chain omega-3 fatty acids and atrophy of the medial temporal lobe. Neurology 79:642–650

    PubMed  CAS  Article  Google Scholar 

  7. Martins JG 2009 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 28:525–542

    PubMed  CAS  Google Scholar 

  8. Sublette ME, Ellis SP, Geant AL, Mann JJ 2011 Meta-analysis of the effects of eicosapentaenoic acid (EPA) in clinical trials in depression. J Clin Psychiatry 72:1577–1584

    PubMed  CAS  Article  Google Scholar 

  9. Calon F 2011 Omega-3 polyunsaturated fatty acids in Alzheimer’s disease: key questions and partial answers. Curr Alzheimer Res 8:470–478

    PubMed  CAS  Article  Google Scholar 

  10. Burdge GC, Calder PC 2005 Conversion of alpha-linolenic acid to longer-chain polyunsaturated fatty acids in human adults. Reprod Nutr Dev 45:581–597

    PubMed  CAS  Article  Google Scholar 

  11. Arterburn LM, Hall EB, Oken H 2006 Distribution, interconversion, and dose response of n-3 fatty acids in humans. Am J Clin Nutr 83:1467S–1476S

    PubMed  CAS  Google Scholar 

  12. Sanders TA 2009 DHA status of vegetarians. Prostaglandins Leukot Essent Fatty Acids 81:137–141

    PubMed  CAS  Article  Google Scholar 

  13. Kim HW, Rao JS, Rapoport SI, Igarashi M 2011 Regulation of rat brain polyunsaturated fatty acid (PUFA) metabolism during graded dietary n-3 PUFA deprivation. Prostaglandins Leukot Essent Fatty Acids 85:361–368

    PubMed  CAS  Article  Google Scholar 

  14. James MJ, Ursin VM, Cleland LG 2003 Metabolism of stearidonic acid in human subjects: comparison with the metabolism of other n-3 fatty acids. Am J Clin Nutr 77:1140–1145

    PubMed  CAS  Google Scholar 

  15. Whelan J, Gouffon J, Zhao Y 2012 Effects of dietary stearidonic acid on biomarkers of lipid metabolism. J Nutr 142:630S–634S

    PubMed  CAS  Article  Google Scholar 

  16. Tur JA, Bibiloni MM, Sureda A, Pons A 2012 Dietary sources of omega 3 fatty acids: public health risks and benefits. Br J Nutr 107Suppl 2:S23–S52

    PubMed  CAS  Article  Google Scholar 

  17. Racine RA, Deckelbaum RJ 2007 Sources of the very-long-chain unsaturated omega-3 fatty acids: eicosapentaenoic acid and docosahexaenoic acid. Curr Opin Clin Nutr Metab Care 10:123–128

    PubMed  CAS  Article  Google Scholar 

  18. Weaver KL, Ivester P, Chilton JA, Wilson MD, Pandey P, Chilton FH 2008 The content of favorable and unfavorable polyunsaturated fatty acids found in commonly eaten fish. J Am Diet Assoc 108:1178–1185

    PubMed  CAS  Article  Google Scholar 

  19. Chung H, Nettleton JA, Lemaitre RN, Barr RG, Tsai MY, Tracy RP, Siscovick DS 2008 Frequency and type of seafood consumed influence plasma (n-3) fatty acid concentrations. J Nutr 138:2422–2427

    PubMed  CAS  Article  Google Scholar 

  20. Zargar A, Ito MK 2011 Long chain omega-3 dietary supplements: a review of the National Library of Medicine Herbal Supplement Database. Metab Syndr Relat Disord 9:255–271

    PubMed  CAS  Article  Google Scholar 

  21. Bays HE, Ballantyne CM, Kastelein JJ, Isaacsohn JL, Braeckman RA, Soni PN 2011 Eicosapentaenoic acid ethyl ester (AMR101) therapy in patients with very high triglyceride levels (from the Multi-center, plAcebo-controlled, Randomized, double-blINd, 12-week study with an open-label Extension [MARINE] trial). Am J Cardiol 108:682–690

    PubMed  CAS  Article  Google Scholar 

  22. Davidson MH, Kling D, Maki KC 2011 Novel developments in omega-3 fatty acid-based strategies. Curr Opin Lipidol 22:437–444

    PubMed  CAS  Article  Google Scholar 

  23. Hersher R 2012 Are drugmakers fishing for a market with prescription omega-3s? Nat Med 18:6

    PubMed  CAS  Article  Google Scholar 

  24. Yurko-Mauro K, McCarthy D, Rom D, Nelson EB, Ryan AS, Blackwell A, Salem N, Jr., Stedman M 2010 Beneficial effects of docosahexaenoic acid on cognition in age-related cognitive decline. Alzheimers Dement 6:456–464

    PubMed  CAS  Article  Google Scholar 

  25. Ryan AS, Keske MA, Hoffman JP, Nelson EB 2009 Clinical overview of algaldocosahexaenoic acid: effects on triglyceride levels and other cardiovascular risk factors. Am J Ther 16:183–192

    PubMed  Article  Google Scholar 

  26. Arterburn LM, Oken HA, Bailey HE, Hamersley J, Kuratko CN, Hoffman JP 2008 Algaloil capsules and cooked salmon: nutritionally equivalent sources of docosahexaenoic acid. J Am Diet Assoc 108:1204–1209

    PubMed  CAS  Article  Google Scholar 

  27. Berge JP, Barnathan G 2005 Fatty acids from lipids of marine organisms: molecular biodiversity, roles as biomarkers, biologically active compounds, and economical aspects. Adv Biochem Eng Biotechnol 96:49–125.:49–125

    PubMed  CAS  Google Scholar 

  28. Adarme-Vega TC, Lim DK, Timmins M, Vernen F, Li Y, Schenk PM 2012 Microalgal biofactories: a promising approach towards sustainable omega-3 fatty acid production. Microb Cell Fact 11:96

    PubMed  CAS  Article  Google Scholar 

  29. MacKenzie SA, Belcher LA, Sykes GP, Frame SR, Mukerji P, Gillies PJ 2010 Safety assessment of EPA-rich oil produced from yeast: Results of a 90-day subchronic toxicity study. Regul Toxicol Pharmacol 58:490–500

    PubMed  CAS  Article  Google Scholar 

  30. Kidd PM 2007 Omega-3 DHA and EPA for cognition, behavior, and mood: clinical findings and structural-functional synergies with cell membrane phospholipids. Altern Med Rev 12:207–227

    PubMed  Google Scholar 

  31. Kullenberg D, Taylor LA, Schneider M, Massing U 2012 Health effects of dietary phospholipids. Lipids Health Dis 11:3

    PubMed  Article  CAS  Google Scholar 

  32. Vakhapova V, Richter Y, Cohen T, Herzog Y, Korczyn AD 2011 Safety of phosphatidylserine containing omega-3 fatty acids in non-demented elderly: a double-blind placebo-controlled trial followed by an open-label extension. BMC Neurol 11:79.:79

    PubMed  Article  CAS  Google Scholar 

  33. Schuchardt JP, Schneider I, Meyer H, Neubronner J, von SC, Hahn A 2011 Incorporation of EPA and DHA into plasma phospholipids in response to different omega-3 fatty acid formulations—a comparative bioavailability study of fish oil vs. krill oil. Lipids Health Dis 10:145.:145

    Article  CAS  Google Scholar 

  34. Scheltens P, Twisk JW, Blesa R, Scarpini E, von Arnim CA, Bongers A, Harrison J, Swinkels SH, Stam CJ, de WH, Wurtman RJ, Wieggers RL, Vellas B, Kamphuis PJ 2012 Efficacy of souvenaid in mild Alzheimer’s disease: results from a randomized, controlled trial. J Alzheimers Dis 31:225–236

    PubMed  CAS  Google Scholar 

  35. Cole GM, Ma QL, Frautschy SA 2009 Omega-3 fatty acids and dementia. Prostaglandins Leukot Essent Fatty Acids 81:213–221

    PubMed  CAS  Article  Google Scholar 

  36. Venegas-Caleron M, Sayanova O, Napier JA 2010 An alternative to fish oils: Metabolic engineering of oil-seed crops to produce omega-3 long chain polyunsaturated fatty acids. Prog Lipid Res 49:108–119

    PubMed  CAS  Article  Google Scholar 

  37. Whelan J, Rust C 2006 Innovative dietary sources of n-3 fatty acids. Annu Rev Nutr 26:75–103

    PubMed  CAS  Article  Google Scholar 

  38. McManus A, Merga M, Newton W 2011 Omega-3 fatty acids. What consumers need to know. Appetite 57:80–83

    PubMed  Article  Google Scholar 

  39. Taneja A, Singh H 2012 Challenges for the delivery of long-chain n-3 fatty acids in functional foods. Annu Rev Food Sci Technol 3:105–123

    PubMed  CAS  Article  Google Scholar 

  40. Glisky EL 2007 Changes in Cognitive Function in Human Aging. In: Riddle DR, ed. Brain Aging: Models, Methods, and Mechanisms. Boca Raton (FL): CRC Press

    Google Scholar 

  41. Grady C 2012 The cognitive neuroscience of ageing. Nat Rev Neurosci 13:491–505

    PubMed  CAS  Article  Google Scholar 

  42. Cunnane SC, Plourde M, Pifferi F, Begin M, Feart C, Barberger-Gateau P 2009 Fish, docosahexaenoic acid and Alzheimer’s disease. Prog Lipid Res 48:239–256

    PubMed  CAS  Article  Google Scholar 

  43. Begin ME, Plourde M, Pifferi F, Cunnane SC 2010 What Is the Link between Docosahexaenoic Acid, Cognitive Impairment, and Alzheimer’s Disease in the Elderly? In: Montmayeur JP, le Coutre J, eds. Fat Detection: Taste, Texture, and Post Ingestive Effects. Boca Raton (FL): CRC Press

    Google Scholar 

  44. Danthiir V, Burns NR, Nettelbeck T, Wilson C, Wittert G 2011 The older people, omega-3, and cognitive health (EPOCH) trial design and methodology: a randomised, doubleblind, controlled trial investigating the effect of long-chain omega-3 fatty acids on cognitive ageing and wellbeing in cognitively healthy older adults. Nutr J 20:117

    Article  CAS  Google Scholar 

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

    PubMed  CAS  Article  Google Scholar 

  46. Bowman GL, Silbert LC, Howieson D, Dodge HH, Traber MG, Frei B, Kaye JA, Shannon J, Quinn JF 2012 Nutrient biomarker patterns, cognitive function, and MRI measures of brain aging. Neurology 78:241–249

    PubMed  CAS  Article  Google Scholar 

  47. Laurin D, Verreault R, Lindsay J, Dewailly E, Holub BJ 2003 Omega-3 fatty acids and risk of cognitive impairment and dementia. J Alzheimers Dis 5:315–322

    PubMed  CAS  Google Scholar 

  48. van de Rest O, Spiro A, III, Krall-Kaye E, Geleijnse JM, de Groot LC, Tucker KL 2009 Intakes of (n-3) fatty acids and fatty fish are not associated with cognitive performance and 6-year cognitive change in men participating in the Veterans Affairs Normative Aging Study. J Nutr 139:2329–2336

    PubMed  Article  CAS  Google Scholar 

  49. Cunnane SC, Schneider JA, Tangney C, Tremblay-Mercier J, Fortier M, Bennett DA, Morris MC 2012 Plasma and brain fatty acid profiles in mild cognitive impairment and Alzheimer’s disease. J Alzheimers Dis 29:691–697

    PubMed  CAS  Google Scholar 

  50. Cunnane SC, Chouinard-Watkins R, Castellano CA, Barberger-Gateau P 2012 Docosahexaenoic acid homeostasis, brain aging and Alzheimer’s disease: Can we reconcile the evidence? Prostaglandins Leukot Essent Fatty Acids Epub ahead of print

    Google Scholar 

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

    PubMed  Google Scholar 

  52. Mazereeuw G, Lanctot KL, Chau SA, Swardfager W, Herrmann N 2012 Effects of omega-3 fatty acids on cognitive performance: a meta-analysis. Neurobiol Aging 33:1482–29

    PubMed  CAS  Article  Google Scholar 

  53. Dangour AD, Allen E, Elbourne D, Fasey N, Fletcher AE, Hardy P, Holder GE, Knight R, Letley L, Richards M, Uauy R 2010 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 91:1725–1732

    PubMed  CAS  Article  Google Scholar 

  54. Ronnemaa E, Zethelius B, Vessby B, Lannfelt L, Byberg L, Kilander L 2012 Serum fattyacid composition and the risk of Alzheimer’s disease: a longitudinal population-based study. Eur J Clin Nutr 66:885–890 doi: 10.1038/ejcn.2012.63.

    PubMed  CAS  Article  Google Scholar 

  55. Huang TL, Zandi PP, Tucker KL, Fitzpatrick AL, Kuller LH, Fried LP, Burke GL, Carlson MC 2005 Benefits of fatty fish on dementia risk are stronger for those without APOE epsilon4. Neurology 65:1409–1414

    PubMed  CAS  Article  Google Scholar 

  56. Dangour AD, Andreeva VA, Sydenham E, Uauy R 2012 Omega 3 fatty acids and cognitive health in older people. Br J Nutr 107Suppl 2:S152–S158.:S152–S158

    PubMed  CAS  Article  Google Scholar 

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

    PubMed  CAS  Article  Google Scholar 

  58. Freund-Levi Y, Hjorth E, Lindberg C, Cederholm T, Faxen-Irving G, Vedin I, Palmblad J, Wahlund LO, Schultzberg M, Basun H, Eriksdotter JM 2009 Effects of omega-3 fatty acids on inflammatory markers in cerebrospinal fluid and plasma in Alzheimer’s disease: the OmegAD study. Dement Geriatr Cogn Disord 27:481–490

    PubMed  CAS  Article  Google Scholar 

  59. Freund-Levi Y, Basun H, Cederholm T, Faxen-Irving G, Garlind A, Grut M, Vedin I, Palmblad J, Wahlund LO, Eriksdotter-Jonhagen M 2008 Omega-3 supplementation in mild to moderate Alzheimer’s disease: effects on neuropsychiatric symptoms. Int J Geriatr Psychiatry 23:161–169

    PubMed  Article  Google Scholar 

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

    PubMed  Article  Google Scholar 

  61. Chiu CC, Su KP, Cheng TC, Liu HC, Chang CJ, Dewey ME, Stewart R, Huang SY 2008 The effects of omega-3 fatty acids monotherapy in Alzheimer’s disease and mild cognitive impairment: a preliminary randomized double-blind placebo-controlled study. Prog Neuropsychopharmacol Biol Psychiatry 32:1538–1544

    PubMed  CAS  Article  Google Scholar 

  62. Kotani S, Sakaguchi E, Warashina S, Matsukawa N, Ishikura Y, Kiso Y, Sakakibara M, Yoshimoto T, Guo J, Yamashima T 2006 Dietary supplementation of arachidonic and docosahexaenoic acids improves cognitive dysfunction. Neurosci Res 56:159–164

    PubMed  CAS  Article  Google Scholar 

  63. Sinn N, Milte CM, Street SJ, Buckley JD, Coates AM, Petkov J, Howe PR 2012 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 107:1682–1693

    PubMed  CAS  Article  Google Scholar 

  64. Iadecola C 2010 The overlap between neurodegenerative and vascular factors in the pathogenesis of dementia. Acta Neuropathol 120:287–296

    PubMed  Article  Google Scholar 

  65. Akter K, Lanza EA, Martin SA, Myronyuk N, Rua M, Raffa RB 2011 Diabetes mellitus and Alzheimer’s disease: shared pathology and treatment? Br J Clin Pharmacol 71:365–376

    PubMed  CAS  Article  Google Scholar 

  66. Murray IV, Proza JF, Sohrabji F, Lawler JM 2011 Vascular and metabolic dysfunction in Alzheimer’s disease: a review. Exp Biol Med (Maywood) 236:772–782

    CAS  Article  Google Scholar 

  67. Gorelick PB, Scuteri A, Black SE, Decarli C, Greenberg SM, Iadecola C, Launer LJ, Laurent S, Lopez OL, Nyenhuis D, Petersen RC, Schneider JA, Tzourio C, Arnett DK, Bennett DA, Chui HC, Higashida RT, Lindquist R, Nilsson PM, Roman GC, Sellke FW, Seshadri S 2011 Vascular contributions to cognitive impairment and dementia: a statement for healthcare professionals from the american heart association/american stroke association. Stroke 42:2672–2713

    PubMed  Article  Google Scholar 

  68. Lichtenstein AH, Appel LJ, Brands M, Carnethon M, Daniels S, Franch HA, Franklin B, Kris-Etherton P, Harris WS, Howard B, Karanja N, Lefevre M, Rudel L, Sacks F, Van HL, Winston M, Wylie-Rosett J 2006 Summary of American Heart Association Diet and Lifestyle Recommendations revision 2006. Arterioscler Thromb Vasc Biol 26:2186–2191

    PubMed  CAS  Article  Google Scholar 

  69. Kris-Etherton PM, Harris WS, Appel LJ 2003 Omega-3 fatty acids and cardiovascular disease: new recommendations from the American Heart Association. Arterioscler Thromb Vasc Biol 23:151–152

    PubMed  CAS  Article  Google Scholar 

  70. Cicero AF, Ertek S, Borghi C 2009 Omega-3 polyunsaturated fatty acids: their potential role in blood pressure prevention and management. Curr Vasc Pharmacol 7:330–337

    PubMed  CAS  Article  Google Scholar 

  71. Geleijnse JM, Giltay EJ, Grobbee DE, Donders AR, Kok FJ 2002 Blood pressure response to fish oil supplementation: metaregression analysis of randomized trials. J Hypertens 20:1493–1499

    PubMed  CAS  Article  Google Scholar 

  72. Pase MP, Grima NA, Sarris J 2011 Do long-chain n-3 fatty acids reduce arterial stiffness? A meta-analysis of randomised controlled trials. Br J Nutr 106:974–980

    PubMed  CAS  Article  Google Scholar 

  73. Wang C, Harris WS, Chung M, Lichtenstein AH, Balk EM, Kupelnick B, Jordan HS, Lau J 2006 n-3 Fatty acids from fish or fish-oil supplements, but not alpha-linolenic acid, benefit cardiovascular disease outcomes in primary- and secondary-prevention studies: a systematic review. Am J Clin Nutr 84:5–17

    PubMed  CAS  Google Scholar 

  74. Marik PE, Varon J 2009 Omega-3 dietary supplements and the risk of cardiovascular events: a systematic review. Clin Cardiol 32:365–372

    PubMed  Article  Google Scholar 

  75. Martinez-Victoria E, Yago MD 2012 Omega 3 polyunsaturated fatty acids and body weight. Br J Nutr 107 Suppl 2:S107–S116

    Article  CAS  Google Scholar 

  76. Wu JH, Micha R, Imamura F, Pan A, Biggs ML, Ajaz O, Djousse L, Hu B, Mozaffarian D 2012 Omega-3 fatty acids and incident type 2 diabetes: a systematic review and metaanalysis. Br J Nutr 107 Suppl 2:S214–S227

    Article  CAS  Google Scholar 

  77. Miles EA, Calder PC 2012 Influence of marine n-3 polyunsaturated fatty acids on immune function and a systematic review of their effects on clinical outcomes in rheumatoid arthritis. Br J Nutr 107 Suppl 2:S171–S184

    Article  CAS  Google Scholar 

  78. Singer P, Shapiro H, Theilla M, Anbar R, Singer J, Cohen J 2008 Anti-inflammatory properties of omega-3 fatty acids in critical illness: novel mechanisms and an integrative perspective. Intensive Care Med 34:1580–1592

    PubMed  CAS  Article  Google Scholar 

  79. Calder PC 2011 Fatty acids and inflammation: the cutting edge between food and pharma. Eur J Pharmacol 668Suppl 1:S50–S58

    PubMed  CAS  Article  Google Scholar 

  80. Farzaneh-Far R, Lin J, Epel ES, Harris WS, Blackburn EH, Whooley MA 2010 Association of marine omega-3 fatty acid levels with telomeric aging in patients with coronary heart disease. JAMA 303:250–257

    PubMed  CAS  Article  Google Scholar 

  81. Puca AA, Andrew P, Novelli V, Anselmi CV, Somalvico F, Cirillo NA, Chatgilialoglu C, Ferreri C 2008 Fatty acid profile of erythrocyte membranes as possible biomarker of longevity. Rejuvenation Res 11:63–72

    PubMed  CAS  Article  Google Scholar 

  82. Hulbert AJ 2010 Metabolism and longevity: is there a role for membrane fatty acids? Integr Comp Biol 50:808–817

    PubMed  CAS  Article  Google Scholar 

  83. van de Rest O, Geleijnse JM, Kok FJ, van Staveren WA, Olderikkert MG, Beekman AT, de Groot LC 2009 Effect of fish oil supplementation on quality of life in a general population of older Dutch subjects: a randomized, double-blind, placebo-controlled trial. J Am Geriatr Soc 57:1481–1486

    PubMed  Article  Google Scholar 

  84. Yehuda S, Rabinovtz S, Carasso RL, Mostofsky DI 1996 Essential fatty acids preparation (SR-3) improves Alzheimer’s patients quality of life. Int J Neurosci 87:141–149

    PubMed  CAS  Article  Google Scholar 

  85. Lien EL 2009 Toxicology and safety of DHA. Prostaglandins Leukot Essent Fatty Acids 81:125–132

    PubMed  CAS  Article  Google Scholar 

  86. Bernstein AM, Ding EL, Willett WC, Rimm EB 2012 A meta-analysis shows that docosahexaenoic acid from algal oil reduces serum triglycerides and increases HDLcholesterol and LDL-cholesterol in persons without coronary heart disease. J Nutr 142:99–104

    PubMed  CAS  Article  Google Scholar 

  87. Serini S, Fasano E, Piccioni E, Cittadini AR, Calviello G 2011 Dietary n-3 polyunsaturated fatty acids and the paradox of their health benefits and potential harmful effects. Chem Res Toxicol 19:2093–2105

    Article  CAS  Google Scholar 

  88. Jacobsen C 2010 Enrichment of foods with omega-3 fatty acids: a multidisciplinary challenge. Ann N Y Acad Sci 1190:141–150

    PubMed  CAS  Article  Google Scholar 

  89. Frautschy SA, Cole GM 2011 What was lost in translation in the DHA trial is whom you should intend to treat. Alzheimers Res Ther 3:2

    PubMed  Article  Google Scholar 

  90. Cole GM, Ma QL, Frautschy SA 2010 Dietary fatty acids and the aging brain. Nutr Rev 68 Suppl 2:S102–11. doi: 10.1111/j.1753-4887.2010.00345.x.:S102-S111

    Article  Google Scholar 

  91. Oster T, Pillot T 2010 Docosahexaenoic acid and synaptic protection in Alzheimer’s disease mice. Biochim Biophys Acta 1801:791–798

    PubMed  CAS  Article  Google Scholar 

  92. Jicha GA, Markesbery WR 2010 Omega-3 fatty acids: potential role in the management of early Alzheimer’s disease. Clin Interv Aging 5:45–61

    PubMed  CAS  Article  Google Scholar 

  93. Harris WS, Mozaffarian D, Lefevre M, Toner CD, Colombo J, Cunnane SC, Holden JM, Klurfeld DM, Morris MC, Whelan J 2009 Towards establishing dietary reference intakes for eicosapentaenoic and docosahexaenoic acids. J Nutr 139:804S–819S

    PubMed  CAS  Article  Google Scholar 

  94. U.S.Department of Agriculture ARS 2012 Nutrient Intakes from Food: Mean Amounts Consumed per Individual, by Gender and Age, What We Eat in America, NHANES 2009–2010. http://www.ars.usda.gov/ba/bhnrc/fsrg.

  95. Elmadfa I, Kornsteiner M 2009 Dietary fat intake—a global perspective. Ann Nutr Metab 54Suppl 1:8–14

    PubMed  CAS  Article  Google Scholar 

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

    PubMed  CAS  Article  Google Scholar 

  97. van de Rest O, Geleijnse JM, Kok FJ, van Staveren WA, Dullemeijer C, Olderikkert MG, Beekman AT, de Groot CP 2008 Effect of fish oil on cognitive performance in older subjects: a randomized, controlled trial. Neurology 71:430–438

    PubMed  Article  CAS  Google Scholar 

  98. Centers for Disease Control and Prevention 2012 Second National Report on Biochemical Indicators of Diet and Nutrition in the U.S. Population. http://www.cdc.gov/nutritionreport.

  99. Barberger-Gateau P, Samieri C, Feart C, Plourde M 2011 Dietary omega 3 polyunsaturated fatty acids and Alzheimer’s disease: interaction with apolipoprotein E genotype. Curr Alzheimer Res 8:479–491

    PubMed  CAS  Article  Google Scholar 

  100. Olano-Martin E, Anil E, Caslake MJ, Packard CJ, Bedford D, Stewart G, Peiris D, Williams CM, Minihane AM 2010 Contribution of apolipoprotein E genotype and docosahexaenoic acid to the LDL-cholesterol response to fish oil. Atherosclerosis 209:104–110

    PubMed  CAS  Article  Google Scholar 

  101. Plourde M, Vohl MC, Vandal M, Couture P, Lemieux S, Cunnane SC 2009 Plasma n-3 fatty acid response to an n-3 fatty acid supplement is modulated by apoE epsilon4 but not by the common PPAR-alpha L162V polymorphism in men. Br J Nutr 102:1121–1124

    PubMed  CAS  Article  Google Scholar 

  102. Martins JG, Bentsen H, Puri BK 2012 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 Epub ahead of print:doi 10.1038/mp.2012.25

    Google Scholar 

  103. Lin PY, Mischoulon D, Freeman MP, Matsuoka Y, Hibbeln J, Belmaker RH, Su KP 2012 Are omega-3 fatty acids antidepressants or just mood-improving agents? The effect depends upon diagnosis, supplement preparation, and severity of depression. Mol Psychiatry Epub ahead of print:doi: 10.1038/mp.2012.111

    Google Scholar 

  104. Andreeva VA, Galan P, Torres M, Julia C, Hercberg S, Kesse-Guyot E 2012 Supplementation with B vitamins or n-3 fatty acids and depressive symptoms in cardiovascular disease survivors: ancillary findings from the SUpplementation with FOLate, vitamins B-6 and B-12 and/or OMega-3 fatty acids (SU.FOL.OM3) randomized trial. Am J Clin Nutr 96:208–214

    PubMed  CAS  Article  Google Scholar 

  105. Kesse-Guyot E, Touvier M, Andreeva VA, Jeandel C, Ferry M, Hercberg S, Galan P 2012 Cross-sectional but not longitudinal association between n-3 fatty acid intake and depressive symptoms: results from the SU.VI.MAX 2 study. Am J Epidemiol 175:979–987

    PubMed  Article  Google Scholar 

  106. Lewis MD, Hibbeln JR, Johnson JE, Lin YH, Hyun DY, Loewke JD 2011 Suicide deaths of active-duty US military and omega-3 fatty-acid status: a case-control comparison. J Clin Psychiatry 72:1585–1590

    PubMed  CAS  Article  Google Scholar 

  107. Mischoulon D 2011 The impact of omega-3 fatty acids on depressive disorders and suicidality: can we reconcile 2 studies with seemingly contradictory results? J Clin Psychiatry 72:1574–1576

    PubMed  CAS  Article  Google Scholar 

  108. Green KN, Martinez-Coria H, Khashwji H, Hall EB, Yurko-Mauro KA, Ellis L, LaFerla FM 2007 Dietary docosahexaenoic acid and docosapentaenoic acid ameliorate amyloidbeta and tau pathology via a mechanism involving presenilin 1 levels. J Neurosci 27:4385–4395

    PubMed  CAS  Article  Google Scholar 

  109. Simopoulos AP 2008 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

    CAS  Article  Google Scholar 

  110. Ramsden CE, Hibbeln JR, Majchrzak SF, Davis JM 2010 n-6 fatty acid-specific and mixed polyunsaturate dietary interventions have different effects on CHD risk: a metaanalysis of randomised controlled trials. Br J Nutr 104:1586–1600

    PubMed  CAS  Article  Google Scholar 

  111. Harris WS, Mozaffarian D, Rimm E, Kris-Etherton P, Rudel LL, Appel LJ, Engler MM, Engler MB, Sacks F 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 119:902–907

    PubMed  Article  Google Scholar 

  112. Dyerberg J, Madsen P, Moller JM, Aardestrup I, Schmidt EB 2010 Bioavailability of marine n-3 fatty acid formulations. Prostaglandins Leukot Essent Fatty Acids 83:137–141

    PubMed  CAS  Article  Google Scholar 

  113. Neubronner J, Schuchardt JP, Kressel G, Merkel M, von SC, Hahn A 2011 Enhanced increase of omega-3 index in response to long-term n-3 fatty acid supplementation from triacylglycerides versus ethyl esters. Eur J Clin Nutr 65:247–254

    PubMed  CAS  Article  Google Scholar 

  114. Ouellet M, Emond V, Chen CT, Julien C, Bourasset F, Oddo S, LaFerla F, Bazinet RP, Calon F 2009 Diffusion of docosahexaenoic and eicosapentaenoic acids through the bloodbrain barrier: An in situ cerebral perfusion study. Neurochem Int 55:476–482

    PubMed  CAS  Article  Google Scholar 

  115. Chen CT, Liu Z, Ouellet M, Calon F, Bazinet RP 2009 Rapid beta-oxidation of eicosapentaenoic acid in mouse brain: an in situ study. Prostaglandins Leukot Essent Fatty Acids 80:157–163

    PubMed  CAS  Article  Google Scholar 

  116. Chen CT, Liu Z, Bazinet RP 2011 Rapid de-esterification and loss of eicosapentaenoic acid from rat brain phospholipids: an intracerebroventricular study. J Neurochem 116:363–373

    PubMed  CAS  Article  Google Scholar 

  117. Bazan NG, Scott BL 1990 Dietary omega-3 fatty acids and accumulation of docosahexaenoic acid in rod photoreceptor cells of the retina and at synapses. Ups J Med Sci Suppl 48:97–107

    PubMed  CAS  Google Scholar 

  118. Umhau JC, Zhou W, Carson RE, Rapoport SI, Polozova A, Demar J, Hussein N, Bhattacharjee AK, Ma K, Esposito G, Majchrzak S, Herscovitch P, Eckelman WC, Kurdziel KA, Salem N, Jr. 2009 Imaging incorporation of circulating docosahexaenoic acid into the human brain using positron emission tomography. J Lipid Res 50:1259–1268

    PubMed  CAS  Article  Google Scholar 

  119. Rapoport SI, Ramadan E, Basselin M 2011 Docosahexaenoic acid (DHA) incorporation into the brain from plasma, as an in vivo biomarker of brain DHA metabolism and neurotransmission. Prostaglandins Other Lipid Mediat 96:109–113

    PubMed  CAS  Article  Google Scholar 

  120. Rapoport SI 2012 Translational studies on regulation of brain docosahexaenoic acid (DHA) metabolism in vivo. Prostaglandins Leukot Essent Fatty Acids Epub ahead of print

    Google Scholar 

  121. Kuratko CN, Salem N, Jr. 2009 Biomarkers of DHA status. Prostaglandins Leukot Essent Fatty Acids 81:111–118

    PubMed  CAS  Article  Google Scholar 

  122. Serra-Majem L, Nissensohn M, Overby NC, Fekete K 2012 Dietary methods and biomarkers of omega 3 fatty acids: a systematic review. Br J Nutr 107Suppl 2:S64–S76.:S64–S76

    PubMed  CAS  Article  Google Scholar 

  123. Plourde M, Chouinard-Watkins R, Vandal M, Zhang Y, Lawrence P, Brenna JT, Cunnane SC 2011 Plasma incorporation, apparent retroconversion and beta-oxidation of 13Cdocosahexaenoic acid in the elderly. Nutr Metab (Lond) 8:5.:5

    CAS  Article  Google Scholar 

  124. Hall JC, Priestley JV, Perry VH, Michael-Titus AT 2012 Docosahexaenoic acid, but not eicosapentaenoic acid, reduces the early inflammatory response following compression spinal cord injury in the rat. J Neurochem 121:738–750

    PubMed  CAS  Article  Google Scholar 

  125. Michael-Titus AT 2007 Omega-3 fatty acids and neurological injury. Prostaglandins Leukot Essent Fatty Acids 77:295–300

    PubMed  CAS  Article  Google Scholar 

  126. Andrieu S, Aboderin I, Baeyens JP, Beard J, Benetos A, Berrut G, Brainin M, Cha HB, Chen LK, Du P, Forette B, Forette F, Franco A, Fratiglioni L, Gillette-Guyonnet S, Gold G, Gomez F, Guimaraes R, Gustafson D, Khachaturian A, Luchsinger J, Mangialasche F, Mathiex-Fortunet H, Michel JP, Richard E, Schneider LS, Solomon A, Vellas B 2011 IAGG workshop: health promotion program on prevention of late onset dementia. J Nutr Health Aging 15:562–575

    PubMed  CAS  Article  Google Scholar 

  127. Manson JE, Bassuk SS, Lee IM, Cook NR, Albert MA, Gordon D, Zaharris E, Macfadyen JG, Danielson E, Lin J, Zhang SM, Buring JE 2012 The VITamin D and OmegA-3 TriaL (VITAL): rationale and design of a large randomized controlled trial of vitamin D and marine omega-3 fatty acid supplements for the primary prevention of cancer and cardiovascular disease. Contemp Clin Trials 33:159–171

    PubMed  CAS  Article  Google Scholar 

  128. Quehenberger O, Dennis EA 2011 The human plasma lipidome. N Engl J Med 365:1812–1823

    PubMed  CAS  Article  Google Scholar 

  129. Hoffman DR, Boettcher JA, Diersen-Schade DA 2009 Toward optimizing vision and cognition in term infants by dietary docosahexaenoic and arachidonic acid supplementation: a review of randomized controlled trials. Prostaglandins Leukot Essent Fatty Acids 81:151–158

    PubMed  CAS  Article  Google Scholar 

  130. Ryan AS, Astwood JD, Gautier S, Kuratko CN, Nelson EB, Salem N, Jr. 2010 Effects of long-chain polyunsaturated fatty acid supplementation on neurodevelopment in childhood: a review of human studies. Prostaglandins Leukot Essent Fatty Acids 82:305–314

    PubMed  CAS  Article  Google Scholar 

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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 (2013). https://doi.org/10.1007/s12603-012-0431-3

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Key words

  • DHA
  • EPA
  • dementia
  • omega-3
  • fish