Fish consumption, long-chain omega-3 fatty acids and risk of cognitive decline or Alzheimer disease: a complex association

Abstract

Long-chain omega-3 fatty acids could have neuroprotective properties against dementia, which is becoming a major global public health issue. We conducted a systematic review of the literature to establish the association between eating fish (a source of long-chain omega-3 fatty acids) or taking long-chain omega-3 fatty acid supplements and the risk of cognitive decline or Alzheimer disease (AD). We identified eleven observational studies and four clinical trials. All three observational studies that used cognitive decline as an outcome reported significant benefits, whereas only four of eight observational studies that used incidence of AD or dementia as an outcome reported positive findings. None of four small clinical trials provided convincing evidence for the use of this approach in the prevention or treatment of any form of dementia. In summary, the existing data favor a role for long-chain omega-3 fatty acids in slowing cognitive decline in elderly individuals without dementia, but not for the prevention or treatment of dementia (including AD). This apparent dichotomy might reflect differences in study designs with regard to participants, dosages, the ratio of long-chain omega-3 to omega-6 fatty acids, or the choice of outcome measurements. Large clinical trials of extended duration should help to provide definitive answers.

Key Points

  • Long-chain omega-3 fatty acids are essential for normal brain development

  • Levels of omega-3 fatty acids are decreased in the brains of patients with Alzheimer disease (AD)

  • Biological studies and animal models suggest that omega-3 fatty acids have a role in primary prevention of cognitive decline by improving blood flow, decreasing inflammation and/or reducing amyloid-β pathology

  • Evidence from observational studies in humans favors consumption of long-chain omega-3 fatty acids to reduce cognitive decline with aging

  • The clinical trials conducted to date have shown no benefits of omega-3 fatty acids for secondary prevention or treatment of AD

  • Larger, ongoing, randomized trials should provide more-definitive answers regarding the use of long-chain omega-3 fatty acids for the prevention and/or treatment of AD

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Figure 1: Proposed neuroprotective properties of DHA.
Figure 2: Summary of observational studies of the effects of long-chain omega-3 fatty acids on the risk of developing Alzheimer disease.

References

  1. 1

    Das UN (2006) Essential fatty acids—a review. Curr Pharm Biotechnol 7: 467–482

    CAS  Article  Google Scholar 

  2. 2

    Grossfield A et al. (2006) A role for direct interactions in the modulation of rhodopsin by omega-3 polyunsaturated lipids. Proc Natl Acad Sci USA 103: 4888–4893

    CAS  Article  Google Scholar 

  3. 3

    Stillwell W et al. (2005) Docosahexaenoic acid affects cell signaling by altering lipid rafts. Reprod Nutr Dev 45: 559–579

    CAS  Article  Google Scholar 

  4. 4

    Chalon S (2006) Omega-3 fatty acids and monoamine neurotransmission. Prostaglandins Leukot Essent Fatty Acids 75: 259–269

    CAS  Article  Google Scholar 

  5. 5

    Bazan NG (2006) Cell survival matters: docosahexaenoic acid signaling, neuroprotection and photoreceptors. Trends Neurosci 29: 263–271

    Article  Google Scholar 

  6. 6

    Coti Bertrand P et al. (2006) Maternal dietary (n-3) fatty acid deficiency alters neurogenesis in the embryonic rat brain. J Nutr 136: 1570–1575

    Article  Google Scholar 

  7. 7

    Innis SM (2007) Dietary (n-3) fatty acids and brain development. J Nutr 137: 855–859

    CAS  Article  Google Scholar 

  8. 8

    Horrocks LA and Yeo YK (1999) Health benefits of docosahexaenoic acid (DHA). Pharmacol Res 40: 211–225

    CAS  Article  Google Scholar 

  9. 9

    McCann JC and Ames BN (2005) Is docosahexaenoic acid, an n-3 long-chain polyunsaturated fatty acid, required for development of normal brain function? An overview of evidence from cognitive and behavioral tests in humans and animals. Am J Clin Nutr 82: 281–295

    CAS  Article  Google Scholar 

  10. 10

    Uauy R and Dangour AD (2006) Nutrition in brain development and aging: role of essential fatty acids. Nutr Rev 64 (Suppl): S24–S33

    Article  Google Scholar 

  11. 11

    Giusto NM et al. (2002) Age-associated changes in central nervous system glycerolipid composition and metabolism. Neurochem Res 27: 1513–1523

    CAS  Article  Google Scholar 

  12. 12

    Conquer J A et al. (2000) Fatty acid analysis of blood plasma of patients with Alzheimer's disease, other types of dementia, and cognitive impairment. Lipids 35: 1305–1312

    Article  Google Scholar 

  13. 13

    Tully AM et al. (2003) Low serum cholesteryl ester-docosahexaenoic acid levels in Alzheimer's disease: a case–control study. Br J Nutr 89: 483–489

    CAS  Article  Google Scholar 

  14. 14

    Connor WE et al. (1990) Dietary effects on brain fatty acid composition: the reversibility of n-3 fatty acid deficiency and turnover of docosahexaenoic acid in the brain, erythrocytes, and plasma of rhesus monkeys. J Lipid Res 31: 237–247

    CAS  PubMed  Google Scholar 

  15. 15

    Gamoh S et al. (1999) Chronic administration of docosahexaenoic acid improves reference memory-related learning ability in young rats. Neuroscience 93: 237–241

    CAS  Article  Google Scholar 

  16. 16

    Tsukada H et al. (2000) Docosahexaenoic acid (DHA) improves the age-related impairment of the coupling mechanism between neuronal activation and functional cerebral blood flow response: a PET study in conscious monkeys. Brain Res 862: 180–186

    CAS  Article  Google Scholar 

  17. 17

    Katayama Y et al. (1997) Effect of long-term administration of ethyl eicosapentate (EPA-E) on local cerebral blood flow and glucose utilization in stroke-prone spontaneously hypertensive rats (SHRSP). Brain Res 761: 300–305

    CAS  Article  Google Scholar 

  18. 18

    Hooper L et al. (2006) Risks and benefits of omega 3 fats for mortality, cardiovascular disease, and cancer: systematic review. BMJ 332: 752–760

    Article  Google Scholar 

  19. 19

    Marchioli R et al. (2002) Early protection against sudden death by n-3 polyunsaturated fatty acids after myocardial infarction: time-course analysis of the results of the Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto Miocardico (GISSI)-Prevenzione. Circulation 105: 1897–1903

    CAS  Article  Google Scholar 

  20. 20

    Leaf A and Weber PC (1988) Cardiovascular effects of n-3 fatty acids. N Engl J Med 318: 549–557

    CAS  Article  Google Scholar 

  21. 21

    Wang C et al. (2006) n-3 Fatty acids from fish or fish-oil supplements, but not α-linolenic acid, benefit cardiovascular disease outcomes in primary- and secondary-prevention studies: a systematic review. Am J Clin Nutr 84: 5–17

    CAS  Article  Google Scholar 

  22. 22

    Kris-Etherton PM et al. (2002) Fish consumption, fish oil, omega-3 fatty acids, and cardiovascular disease. Circulation 106: 2747–2757

    Article  Google Scholar 

  23. 23

    Lichtenstein AH et al. (2006) Diet and lifestyle recommendations revision 2006: a scientific statement from the American Heart Association Nutrition Committee. Circulation 114: 82–96

    Article  Google Scholar 

  24. 24

    Virtanen JK et al. (2008) Fish consumption and risk of subclinical brain abnormalities on MRI in older adults. Neurology 71: 439–446

    CAS  Article  Google Scholar 

  25. 25

    He K et al. (2004) Fish consumption and incidence of stroke: a meta-analysis of cohort studies. Stroke 35: 1538–1542

    Article  Google Scholar 

  26. 26

    Callegari PE and Zurier RB (1991) Botanical lipids: potential role in modulation of immunologic responses and inflammatory reactions. Rheum Dis Clin North Am 17: 415–425

    CAS  Google Scholar 

  27. 27

    Gil A (2002) Polyunsaturated fatty acids and inflammatory diseases. Biomed Pharmacother 56: 388–396

    CAS  Article  Google Scholar 

  28. 28

    Namazi MR (2004) The beneficial and detrimental effects of linoleic acid on autoimmune disorders. Autoimmunity 37: 73–75

    CAS  Article  Google Scholar 

  29. 29

    Mertin J et al. (1985) Nutrition and immunity: the immunoregulatory effect of n-6 essential fatty acids is mediated through prostaglandin E. Int Arch Allergy Appl Immunol 77: 390–395

    CAS  Article  Google Scholar 

  30. 30

    Santoli D and Zurier RB (1989) Prostaglandin E precursor fatty acids inhibit human IL-2 production by a prostaglandin E-independent mechanism. J Immunol 143: 1303–1309

    CAS  Google Scholar 

  31. 31

    Rossetti RG et al. (1997) Oral administration of unsaturated fatty acids: effects on human peripheral blood T lymphocyte proliferation. J Leukoc Biol 62: 438–443

    CAS  Article  Google Scholar 

  32. 32

    Endres S et al. (1989) The effect of dietary supplementation with n-3 polyunsaturated fatty acids on the synthesis of interleukin-1 and tumor necrosis factor by mononuclear cells. N Engl J Med 320: 265–271

    CAS  Article  Google Scholar 

  33. 33

    DeLuca P et al. (1999) Effects of gammalinolenic acid on interleukin-1 beta and tumor necrosis factor-alpha secretion by stimulated human peripheral blood monocytes: studies in vitro and in vivo. J Investig Med 47: 246–250

    CAS  Google Scholar 

  34. 34

    Ferrante A et al. (1994) Neutrophil migration inhibitory properties of polyunsaturated fatty acids. The role of fatty acid structure, metabolism, and possible second messenger systems. J Clin Invest 93: 1063–1070

    CAS  Article  Google Scholar 

  35. 35

    Yaffe K et al. (2004) The metabolic syndrome, inflammation, and risk of cognitive decline. JAMA 292: 2237–2242

    CAS  Article  Google Scholar 

  36. 36

    Akiyama H et al. (2000) Inflammation and Alzheimer's disease. Neurobiol Aging 21: 383–421

    CAS  Article  Google Scholar 

  37. 37

    Blok WL et al. (1996) Modulation of inflammation and cytokine production by dietary (n-3) fatty acids. J Nutr 126: 1515–1533

    Article  Google Scholar 

  38. 38

    Cole GM et al. (2005) Prevention of Alzheimer's disease: omega-3 fatty acid and phenolic anti-oxidant interventions. Neurobiol Aging 26 (Suppl 1): S133–S136

    CAS  Article  Google Scholar 

  39. 39

    Corrigan FM et al. (1991) Essential fatty acids in Alzheimer's disease. Ann NY Acad Sci 640: 250–252

    CAS  Article  Google Scholar 

  40. 40

    Requejo AM et al. (2003) Influence of nutrition on cognitive function in a group of elderly, independently living people. Eur J Clin Nutr 57 (Suppl 1): S54–S57

    CAS  Article  Google Scholar 

  41. 41

    Manzato E et al. (2003) Cognitive functions are not affected by dietary fatty acids in elderly subjects in the Pro.V.A. study population. Aging Clin Exp Res 15: 83–86

    Article  Google Scholar 

  42. 42

    Bosman GJ et al. (1991) Erythrocyte membrane characteristics indicate abnormal cellular aging in patients with Alzheimer's disease. Neurobiol Aging 12: 13–18

    CAS  Article  Google Scholar 

  43. 43

    Otsuka M et al. (2002) Similarities and differences between Alzheimer's disease and vascular dementia from the viewpoint of nutrition. Ann NY Acad Sci 977: 155–161

    CAS  Article  Google Scholar 

  44. 44

    Kalmijn S et al. (2004) Dietary intake of fatty acids and fish in relation to cognitive performance at middle age. Neurology 62: 275–280

    CAS  Article  Google Scholar 

  45. 45

    Yehuda S et al. (1996) Essential fatty acids preparation (SR-3) improves Alzheimer's patients quality of life. Int J Neurosci 87: 141–149

    CAS  Article  Google Scholar 

  46. 46

    Kalmijn S et al. (1997) Dietary fat intake and the risk of incident dementia in the Rotterdam Study. Ann Neurol 42: 776–782

    CAS  Article  Google Scholar 

  47. 47

    Engelhart MJ et al. (2002) Diet and risk of dementia: does fat matter? The Rotterdam Study. Neurology 59: 1915–1921

    Article  Google Scholar 

  48. 48

    Barberger-Gateau P et al. (2002) Fish, meat, and risk of dementia: cohort study. BMJ 325: 932–933

    Article  Google Scholar 

  49. 49

    Laurin D et al. (2003) Omega-3 fatty acids and risk of cognitive impairment and dementia. J Alzheimers Dis 5: 315–322

    CAS  Article  Google Scholar 

  50. 50

    Morris MC et al. (2003) Dietary fats and the risk of incident Alzheimer disease. Arch Neurol 60: 194–200

    Article  Google Scholar 

  51. 51

    Huang TL et al. (2005) Benefits of fatty fish on dementia risk are stronger for those without APOE ε4. Neurology 65: 1409–1414

    Article  Google Scholar 

  52. 52

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

    Article  Google Scholar 

  53. 53

    Barberger-Gateau P et al. (2007) Dietary patterns and risk of dementia: the Three-City cohort study. Neurology 69: 1921–1930

    CAS  Article  Google Scholar 

  54. 54

    Samieri C et al. (2008) Low plasma eicosapentaenoic acid and depressive symptomatology are independent predictors of dementia risk. Am J Clin Nutr 88: 714–721

    CAS  Article  Google Scholar 

  55. 55

    Heude B et al. (2003) Cognitive decline and fatty acid composition of erythrocyte membranes—the EVA Study. Am J Clin Nutr 77: 803–808

    CAS  Article  Google Scholar 

  56. 56

    Morris MC et al. (2005) Fish consumption and cognitive decline with age in a large community study. Arch Neurol 62: 1849–1853

    Article  Google Scholar 

  57. 57

    van Gelder BM et al. (2007) Fish consumption, n-3 fatty acids, and subsequent 5-y cognitive decline in elderly men: the Zutphen Elderly Study. Am J Clin Nutr 85: 1142–1147

    CAS  Article  Google Scholar 

  58. 58

    Terano T et al. (1999) Docosahexaenoic acid supplementation improves the moderately severe dementia from thrombotic cerebrovascular diseases. Lipids 34 (Suppl): S345–S346

    CAS  Article  Google Scholar 

  59. 59

    Kotani S et al. (2006) Dietary supplementation of arachidonic and docosahexaenoic acids improves cognitive dysfunction. Neurosci Res 56: 159–164

    Article  Google Scholar 

  60. 60

    Freund-Levi Y et al. (2006) Omega-3 fatty acid treatment in 174 patients with mild to moderate Alzheimer disease: OmegAD study: a randomized double-blind trial. Arch Neurol 63: 1402–1408

    Article  Google Scholar 

  61. 61

    van de Rest O et al. (2008) Effect of fish oil on cognitive performance in older subjects: a randomized, controlled trial. Neurology 71: 430–438

    CAS  Article  Google Scholar 

  62. 62

    Dangour AD et al. (2006) A randomised controlled trial investigating the effect of n-3 long-chain polyunsaturated fatty acid supplementation on cognitive and retinal function in cognitively healthy older people: the Older People And n-3 Long-chain polyunsaturated fatty acids (OPAL) study protocol [ISRCTN72331636]. Nutr J 5: 20

    Article  Google Scholar 

  63. 63

    DHA (docosahexaenoic acid), an omega 3 fatty acid, in slowing the progression of Alzheimer's disease [http://clinicaltrials.gov/ct2/show/ NCT00440050] (accessed 14 January 2009)

  64. 64

    Lim WS et al. Omega 3 fatty acid for the prevention of dementia. Cochrane Database of Systematic Reviews 2006, Issue 1. Art. No.: CD005379. 10.1002/14651858.CD005379.pub2

    Google Scholar 

  65. 65

    Harris WS (2006) The omega-6/omega-3 ratio and cardiovascular disease risk: uses and abuses. Curr Atheroscler Rep 8: 453–459

    CAS  Article  Google Scholar 

  66. 66

    Stanley JC et al. (2007) UK Food Standards Agency Workshop Report: the effects of the dietary n-6:n-3 fatty acid ratio on cardiovascular health. Br J Nutr 98: 1305–1310

    CAS  Article  Google Scholar 

  67. 67

    Griffin MD et al. (2006) Effects of altering the ratio of dietary n-6 to n-3 fatty acids on insulin sensitivity, lipoprotein size, and postprandial lipemia in men and postmenopausal women aged 45–70 y: the OPTILIP Study. Am J Clin Nutr 84: 1290–1298

    CAS  Article  Google Scholar 

  68. 68

    Rosell MS et al. (2005) Long-chain n-3 polyunsaturated fatty acids in plasma in British meat-eating, vegetarian, and vegan men. Am J Clin Nutr 82: 327–334

    CAS  Article  Google Scholar 

  69. 69

    Whalley LJ et al. (2008) n-3 Fatty acid erythrocyte membrane content, APOE ε4, and cognitive variation: an observational follow-up study in late adulthood. Am J Clin Nutr 87: 449–454

    CAS  Article  Google Scholar 

  70. 70

    Troncoso JC et al. (2008) Effect of infarcts on dementia in the Baltimore longitudinal study of aging. Ann Neurol 64: 168–176

    Article  Google Scholar 

  71. 71

    Whitmer RA et al. (2008) Central obesity and increased risk of dementia more than three decades later. Neurology 71: 1057–1064

    CAS  Article  Google Scholar 

  72. 72

    Schneider JA et al. (2007) Mixed brain pathologies account for most dementia cases in community-dwelling older persons. Neurology 69: 2197–2204

    Article  Google Scholar 

  73. 73

    Aizenstein HJ et al. (2008) Frequent amyloid deposition without significant cognitive impairment among the elderly. Arch Neurol 65: 1509–1517

    Article  Google Scholar 

  74. 74

    Bjelakovic G et al. (2007) Mortality in randomized trials of antioxidant supplements for primary and secondary prevention: systematic review and meta-analysis. JAMA 297: 842–857

    Article  Google Scholar 

  75. 75

    Knopman DS (2008) Go to the head of the class to avoid vascular dementia and skip diabetes and obesity. Neurology 71: 1046–1047

    Article  Google Scholar 

  76. 76

    Wilson RS et al. (2007) Relation of cognitive activity to risk of developing Alzheimer disease. Neurology 69: 1911–1920

    CAS  Article  Google Scholar 

  77. 77

    Wilson RS et al. (2007) Chronic distress and incidence of mild cognitive impairment. Neurology 68: 2085–2092

    CAS  Article  Google Scholar 

Download references

Acknowledgements

K Yaffe is supported in part by grants from the NIH (AG 031155) and from an anonymous foundation. We thank Tzipora Sofare for her editorial assistance in preparing this manuscript. She provided thoughtful comments, critical feedback, and helped with improving tables and figures.

Author information

Affiliations

Authors

Corresponding author

Correspondence to Majid Fotuhi.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Fotuhi, M., Mohassel, P. & Yaffe, K. Fish consumption, long-chain omega-3 fatty acids and risk of cognitive decline or Alzheimer disease: a complex association. Nat Rev Neurol 5, 140–152 (2009). https://doi.org/10.1038/ncpneuro1044

Download citation

Further reading