Rapid Review Alert November 3, 2010
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 In EPA & DHA Research
Abstract Details

Objective: To determine if supplementation with DHA slowscognitive and functional decline in individuals with AlzheimerDisease.

Design, Setting, and Patients:  A randomized, double-blind,placebo-controlled trial of DHA supplementation in individualswith mild to moderate Alzheimer disease was conducted at 51 U.S. clinical research sites of the Alzheimer’s DiseaseCooperative Study.
Intervention: Participants were randomly assigned to algalDHA at a dose of 2 g/d or to an identical placebo. Duration of treatmentwas 18 months.

Main Outcome Measures:  1) change in the cognitive subscaleof the Alzheimer’s Disease Assessment Scale (ADAS-cog); 2) change in the Clinical Dementia Rating (CDR) sum of boxes; 3) in a subsample of participants, rate of brain atrophy was determined by volumetric magneticresonance imaging

Results: A total of 402 individuals were randomized anda total of 295 participants completed the trial while takingstudy medication (DHA: 171; placebo: 124). 1) Supplementation withDHA had no beneficial effect on rate of change on ADAS-cog score,which increased by a mean of 7.98 points for the DHA group during 18 months versus8.27 points for the placebo group. 2) The CDR sumof boxes score increased by 2.87 points for the DHA group during 18 months compared with 2.93 pointsfor the placebo group. 3) In the subpopulation of participants(DHA: 53; placebo: 49), the rate of brain atrophy was not affectedby treatment with DHA. Individuals in the DHA group had  a meandecline in total brain volume of 24.7 cm3 (95% CI, 21.4-28.0cm3) during 18 months and a 1.32% volumedecline per year compared with 24.0 cm3 for the placebo group during 18 months and a 1.29% volume decline per year. 

Authors' Conclusion: Supplementation with DHA compared with placebo did not slow the rate of cognitive and functional decline in pateints with mild to moderate Alzheimer Disease.

Rapid Review Alert
Alzheimer's disease and dementia
DHA Supplementation and Cognitive Decline in Alzheimer Disease 

Review of:
Quinn JF Raman R Thomas RG Yurko-Mauro K Nelson EB Van Dyck C Galvin JE Emond J Jack Jr CR Weiner M Shinto L and Aisen PS (2010). Docosahexaenoic acid supplementation and cognitive decline in Alzheimer Disease: A randomized trial. JAMA 304:1903-1911. 

Take-Home Message

  • Despite the current results, given the enormous scientific body of evidence demonstrating multiple health benefits of long-chain omega-3 supplementation across the lifespan, individuals should not wait for the onset of illness to commence supplementing their diets.  Remember, “An ounce of prevention is worth a pound of cure.”
  • An absence of a cognitive benefit in the present study does not exclude the possibility that supplementation with DHA prior to the onset of Alzheimer disease (AD) could provide a neuroprotective benefit (e.g. delayed onset of symptoms, delayed progression of disease, etc…).  

Study Limitations
  • Supplementation prior to the onset of symptoms may have resulted in a different outcome.
    • Whaley et al., 2004 reported on an observational study of subjects born in 1936 whose mental ability was tested in 1947 and who were followed up in 2000–2001, at which time cognition, diet, food supplement use, and risk factors for vascular disease were assessed. In a nested case-control study, fish-oil users were matched with nonusers and cognitive function was related to erythrocyte n-3 fatty acid composition, thus suggesting better cognitive aging.
    • A review by Jicha and Markesbery (2010) addresses extent of cognitive decline as it relates to the stage of disease that supplementation commences.
    • In an editorial published in the same issue of JAMA, it was suggested that dementia be viewed more in a life course model with earlier intervention for those at risk yielding greater results (Yaffe, 2010).
  • Given that previous research has demonstrated a dementia-protective effect of omega-3 fatty acids being limited to APOE ε4–negative individuals (Barberger-Gateau et al., 2007; Huang et al., 2005; Whalley et al., 2008), more emphasis should have been placed on the reporting of the results of this subgroup. For the primary outcome measure of change in Alzheimer’s Disease Assessment Scale (ADAS-cog), those receiving DHA in the APOE ε4–negative group had a significantly lower decline in mean change over 18 months (6.23 points for 61 participants in the DHA group vs 10.11 points for 48 participants in the placebo group). This differential DHA effect was also evident for the secondary outcome measurement of the Mini-Mental State Examination (MMSE) score (−3.36 in the DHA group vs −5.12 in the placebo group).
  • The current study design did not consider dietary fat intake. A recent article from the Journal of Biological Chemistry reported results demonstrating lower levels of brain plaque build-up in mice fed a low-fat diet enriched with DHA compared to mice fed a regular fat diet enriched with DHA (Jicha and Markesbery, 2010). While animals and humans are different, it begs the question as to whether or not the results reported in JAMA would have been different if the study design had incorporated a low-fat diet.
  • Eicosapentaenoic Acid (EPA) was not provided as part of the treatment. There is research to suggest that a high plasma EPA concentration may decrease the risk of dementia (Samieri et al., 2008).  

Suggested Citation

Global Organization for EPA and DHA Omega-3s (2010). Docosahexaenoic Acid Supplementation and Cognitive Decline in Alzheimer Disease [Peer commentary on the paper “Docosahexaenoic Acid Supplementation and Cognitive Decline in Alzheimer Disease: A randomized trial” by Quinn JF Raman R Thomas RG Yurko-Mauro K Nelson EB Van Dyck C Galvin JE Emond J Jack Jr CR Weiner M Shinto L and Aisen PS (2010). JAMA 304:1903-1911].


Amtul Z Uhrig M Rozmahel RF and Beyreuther K (2010 Oct 22 Epub ahead of print). Structural basis for the differential effects of omega-3 and omega-6 fatty acids on Abeta production and amyloid plaques. J Biol Chem DOI: 10.1074/jbc.M110.183608 

Barberger-Gateau P Raffaitin C Letenneur L Berr C Tzourio C Dartiques JF and Alperovitch A (2007). Dietary patterns and risk of dementia: The three-city cohort study. Neurology 69:1921-1930.
Huang TL Zandi PP Tucker KL Fitzpatrick AL Kuller LH Fried LP Burke GL and Carlson MC (2005). Benefits of fatty fish on dementia risk are stronger for those without APOE epsilon4. Neurology 65:1409-1414.
Jicha GA and Markesbery WR (2010).Omega-3 fatty acids: potential role in the management of early Alzheimer's disease. Clin Interv Aging 5:45-61.
Samieri C Féart C Letenneur L Dartigues JF Pérès K Auriacombe S Peuchant E Delcourt C and Barberger-Gateau P (2008). Low plasma eicosapentaenoic acid and depressive symptomatology are independent predictors of dementia risk. Am J Clin Nutr 88:714-721.
Whalley LJ Deary IJ Starr JM Wahle KW Rance KA Bourne VJ and Fox HC (2008). n-3 fatty acid erythrocyte membrane content, APOE varepsilon4, and cognitive variation: an observational follow-up study in late adulthood. Am J Clin Nutr 87:449-454.
Whalley LJ Fox HC Wahle KW Starr JM and Deary IJ (2004). Cognitive aging, childhood intelligence, and the use of food supplements: Possible involvement of n-3 fatty acids. Am J Clini Nutr 80:1650-1657.

Yaffe K (2010). Treatment of Alzheimer Disease and prognosis of dementia: Time to translate research to results. JAMA 304:1952-1953.
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