The journal of nutrition, health & aging

, Volume 22, Issue 8, pp 982–988 | Cite as

Defining the Optimal Target Population for Trials of Polyunsaturated Fatty Acid Supplementation Using the Erythrocyte Omega-3 Index: A Step Towards Personalized Prevention of Cognitive Decline?

  • Nicola ColeyEmail author
  • R. Raman
  • M. C. Donohue
  • P. S. Aisen
  • B. Vellas
  • S. Andrieu
  • MAPT/DSA Study Group



to identify the optimal erythrocyte omega-3 index cut-off for predicting cognitive decline and/or polyunsaturated fatty acid (PUFA) treatment response, in order to better define the target population for future dementia prevention trials.

Design & Setting

Secondary exploratory analysis of the randomized controlled MAPT prevention trial.


724 dementia-free subjects aged 70 or older with subjective memory complaints, limitations in one instrumental activity of daily living, and/or slow gait speed.


800mg docosahexaenoic acid (DHA) and 225mg eicosapentaenoic acid (EPA) daily versus placebo.


Erythrocyte omega-3 index was measured at baseline. Cognition was measured over 3 years with a composite cognitive score (mean of 4 z-scores).


Placebo group subjects in the lowest quartile of baseline erythrocyte omega-3 index (i.e. ≤4.83%) underwent significantly more 3-year cognitive decline than the other quartiles (mean composite score difference 0.14, 95%CI [0.00, 0.28], p=0.048). In a ROC curve analysis, the optimal omega-3 index cut-off for predicting notable cognitive decline was 5.3%. There was a consistent but non-significant difference in 3-year cognitive decline of approximately 0.12 points between PUFA-treated and placebo subjects with “low” baseline omega-3 index when the cut-off was set at ≤5.27%.


Dementia-free older adults with an omega-3 index below approximately 5% are at increased risk of cognitive decline, and could be a good target population for testing the cognitive effects of PUFA supplementation.

Key words

Cognition omega-3 trial design prevention tailored therapy 

Supplementary material

12603_2018_1052_MOESM1_ESM.docx (337 kb)
Online supplemental material


  1. 1.
    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.CrossRefPubMedGoogle Scholar
  2. 2.
    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.Google Scholar
  3. 3.
    Heude B, Ducimetiere P, Berr C. Cognitive decline and fatty acid composition of erythrocyte membranes—The EVA Study. Am J Clin Nutr. 2003;77(4):803–8.CrossRefPubMedGoogle Scholar
  4. 4.
    Schaefer EJ, Bongard V, Beiser AS, et al. Plasma phosphatidylcholine docosahexaenoic acid content and risk of dementia and Alzheimer disease: the Framingham Heart Study. Arch Neurol. 2006;63(11):1545–50.CrossRefPubMedGoogle Scholar
  5. 5.
    Tan ZS, Harris WS, Beiser AS, et al. Red blood cell omega-3 fatty acid levels and markers of accelerated brain aging. Neurology. 2012;78(9):658–64.CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Yassine HN, Feng Q, Azizkhanian I, et al. Association of Serum Docosahexaenoic Acid With Cerebral Amyloidosis. JAMA Neurol. 2016;73(10):1208–16.CrossRefPubMedGoogle Scholar
  7. 7.
    Pottala JV, Yaffe K, Robinson JG, Espeland MA, Wallace R, Harris WS. Higher RBC EPA + DHA corresponds with larger total brain and hippocampal volumes: WHIMSMRI study. Neurology. 2014;82(5):435–42.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Andreeva VA, Kesse-Guyot E, Barberger-Gateau P, Fezeu L, Hercberg S, Galan P. Cognitive function after supplementation with B vitamins and long-chain omega-3 fatty acids: ancillary findings from the SU.FOL.OM3 randomized trial. Am J Clin Nutr. 2011;94(1):278–86.CrossRefPubMedGoogle Scholar
  9. 9.
    Andrieu S, Guyonnet S, Coley N, et al. Effect of long-term omega 3 polyunsaturated fatty acid supplementation with or without multidomain intervention on cognitive function in elderly adults with memory complaints (MAPT): a randomised, placebocontrolled trial. Lancet Neurol. 2017;16(5):377–89.CrossRefPubMedGoogle Scholar
  10. 10.
    Dangour AD, Allen E, Elbourne D, et al. 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(6):1725–32.CrossRefPubMedGoogle Scholar
  11. 11.
    van de Rest O, Geleijnse JM, Kok FJ, et al. Effect of fish oil on cognitive performance in older subjects: a randomized, controlled trial. Neurology. 2008;71(6):430–8.CrossRefPubMedGoogle Scholar
  12. 12.
    Freund-Levi Y, Eriksdotter-Jonhagen M, Cederholm T, et al. 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(10):1402–8.CrossRefPubMedGoogle Scholar
  13. 13.
    Quinn JF, Raman R, Thomas RG, et al. Docosahexaenoic acid supplementation and cognitive decline in Alzheimer disease: a randomized trial. JAMA. 2010;304(17):1903–11.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Yurko-Mauro K, McCarthy D, Rom D, et al. Beneficial effects of docosahexaenoic acid on cognition in age-related cognitive decline. Alzheimers Dement. 2010;6(6):456–64.CrossRefPubMedGoogle Scholar
  15. 15.
    Dangour AD, Andreeva VA, Sydenham E, Uauy R. Omega 3 fatty acids and cognitive health in older people. Br J Nutr. 2012;107 Suppl 2:S152–8.CrossRefPubMedGoogle Scholar
  16. 16.
    Coley N, Andrieu S, Gardette V, et al. Dementia prevention: methodological explanations for inconsistent results. Epidemiol Rev. 2008;30:35–66.CrossRefPubMedGoogle Scholar
  17. 17.
    Stonehouse W, Conlon CA, Podd J, et al. DHA supplementation improved both memory and reaction time in healthy young adults: a randomized controlled trial. Am J Clin Nutr. 2013;97(5):1134–43.CrossRefPubMedGoogle Scholar
  18. 18.
    Vellas B, Carrie I, Gillette-Guyonnet S, et al. Mapt Study: A Multidomain Approach for Preventing Alzheimer’s Disease: Design and Baseline Data. The Journal of Prevention of Alzheimer’s Disease. 2014;1(1):13–22.PubMedPubMedCentralGoogle Scholar
  19. 19.
    Lawton MP, Brody EM. Assessment of older people: self-maintaining and instrumental activities of daily living. Gerontologist. 1969;9(3):179–86.CrossRefPubMedGoogle Scholar
  20. 20.
    Folstein MF, Folstein SE, McHugh PR. «Mini-mental state». A practical method for grading the cognitive state of patients for the clinician. Journal of Psychiatric Research. 1975;12(3):189–98.PubMedGoogle Scholar
  21. 21.
    Katz S, Ford AB, Moskowitz RW, Jackson BA, Jaffe MW. Studies of Illness in the Aged. The Index of Adl: A Standardized Measure of Biological and Psychosocial Function. JAMA. 1963;185:914–9.PubMedGoogle Scholar
  22. 22.
    Grober E, Buschke H, Crystal H, Bang S, Dresner R. Screening for dementia by memory testing. Neurology. 1988;38(6):900–3.CrossRefPubMedGoogle Scholar
  23. 23.
    Hughes CP, Berg L, Danziger WL, Coben LA, Martin RL. A new clinical scale for the staging of dementia. The British Journal of Psychiatry: the journal of mental science. 1982;140:566–72.CrossRefGoogle Scholar
  24. 24.
    Wechsler D. Wechsler adult intelligence scale-revised. New York: Psychological Corp. 1981.Google Scholar
  25. 25.
    Guralnik JM, Ferrucci L, Pieper CF, et al. Lower extremity function and subsequent disability: consistency across studies, predictive models, and value of gait speed alone compared with the short physical performance battery. The Journals of Gerontology Series A, Biological Sciences and Medical Sciences. 2000;55(4):M221–31.CrossRefPubMedGoogle Scholar
  26. 26.
    Fried LP, Ferrucci L, Darer J, Williamson JD, Anderson G. Untangling the concepts of disability, frailty, and comorbidity: implications for improved targeting and care. The Journals of Gerontology Series A, Biological Sciences and Medical Sciences. 2004;59(3):255–63.CrossRefPubMedGoogle Scholar
  27. 27.
    Yesavage JA, Brink TL, Rose TL, et al. Development and validation of a geriatric depression screening scale: a preliminary report. Journal of Psychiatric Research. 1982;17(1):37–49.CrossRefPubMedGoogle Scholar
  28. 28.
    Coley N, Gallini A, Ousset PJ, Vellas B, Andrieu S, GuidAge study g. Evaluating the clinical relevance of a cognitive composite outcome measure: An analysis of 1414 participants from the 5-year GuidAge Alzheimer’s prevention trial. Alzheimers Dement. 2016;12(12):1216–25.CrossRefPubMedGoogle Scholar
  29. 29.
    van Schoor NM, Comijs HC, Llewellyn DJ, Lips P. Cross-sectional and longitudinal associations between serum 25-hydroxyvitamin D and cognitive functioning. Int Psychogeriatr. 2016;28(5):759–68.CrossRefPubMedGoogle Scholar
  30. 30.
    Nettiksimmons J, Ayonayon H, Harris T, et al. Development and validation of risk index for cognitive decline using blood-derived markers. Neurology. 2015;84(7):696–702.CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Youden WJ. Index for rating diagnostic tests. Cancer. 1950;3(1):32–5.CrossRefPubMedGoogle Scholar
  32. 32.
    Lukaschek K, von Schacky C, Kruse J, Ladwig KH. Cognitive Impairment Is Associated with a Low Omega-3 Index in the Elderly: Results from the KORA-Age Study. Dement Geriatr Cogn Disord. 2016;42(3-4):236–45.CrossRefPubMedGoogle Scholar
  33. 33.
    Harris WS. The omega-3 index as a risk factor for coronary heart disease. Am J Clin Nutr. 2008;87(6):1997S–2002S.CrossRefPubMedGoogle Scholar
  34. 34.
    Harris WS, Von Schacky C. The Omega-3 Index: a new risk factor for death from coronary heart disease? Prev Med. 2004;39(1):212–20.CrossRefPubMedGoogle Scholar
  35. 35.
    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(2):330–40.CrossRefPubMedGoogle Scholar
  36. 36.
    Abubakari AR, Naderali MM, Naderali EK. Omega-3 fatty acid supplementation and cognitive function: are smaller dosages more beneficial? Int J Gen Med. 2014;7:463–73.PubMedPubMedCentralGoogle Scholar
  37. 37.
    Yurko-Mauro K, Alexander DD, Van Elswyk ME. Docosahexaenoic acid and adult memory: a systematic review and meta-analysis. PLoS One. 2015;10(3):e0120391.CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    EFSA Panel on Dietetic Products, Nutrition and Allergies (NDA). Scientific Opinion related to the Tolerable Upper Intake Level of eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA) and docosapentaenoic acid (DPA). EFSA Journal. 2012;10(7):2815.Google Scholar
  39. 39.
    Katan MB, Deslypere JP, van Birgelen AP, Penders M, Zegwaard M. Kinetics of the incorporation of dietary fatty acids into serum cholesteryl esters, erythrocyte membranes, and adipose tissue: an 18-month controlled study. J Lipid Res. 1997;38(10):2012–22.PubMedGoogle Scholar
  40. 40.
    Harris WS, Sands SA, Windsor SL, et al. Omega-3 fatty acids in cardiac biopsies from heart transplantation patients: correlation with erythrocytes and response to supplementation. Circulation. 2004;110(12):1645–9.CrossRefPubMedGoogle Scholar

Copyright information

© Serdi and Springer-Verlag France SAS, part of Springer Nature 2018

Authors and Affiliations

  • Nicola Coley
    • 1
    • 2
    • 5
    Email author
  • R. Raman
    • 3
  • M. C. Donohue
    • 3
  • P. S. Aisen
    • 3
  • B. Vellas
    • 1
    • 4
  • S. Andrieu
    • 1
    • 2
  • MAPT/DSA Study Group
  1. 1.INSERM-Toulouse University UMR1027ToulouseFrance
  2. 2.Toulouse University Hospital, Department of Epidemiology and Public HealthToulouseFrance
  3. 3.Alzheimer’s Therapeutic Research InstituteUniversity of Southern CaliforniaSan DiegoUSA
  4. 4.Toulouse University Hospital, Gérontopôle, Department of Geriatric MedicineToulouseFrance
  5. 5.Faculté de MédecineToulouseFrance

Personalised recommendations