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Higher Omega-3 Status in Middle Age is Associated with Better Brain Structure and Cognitive Function – Interaction with APOE by Dr Charles Desmarchelier, PharmD, PhD

Higher Omega-3 Status in Middle Age is Associated with Better Brain Structure and Cognitive Function

Several epidemiological studies have observed a positive association between omega-3 polyunsaturated fatty acids, particularly docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), status or dietary intake with brain health parameters including better cognitive function, and reduced risk of dementia and Alzheimer’s disease (1). Yet, the results of intervention trials investigating the effect of EPA/DHA supplementation on brain health parameters in individuals with mild cognitive impairment or Alzheimer’s disease dementia have been somewhat disappointing (2). This might be due to the fact that these interventions were conducted too late in the course of the disease.

Therefore, Satizabal et al. (3) measured the association between omega-3 status and parameters of brain health in 2,183 participants from the Third-Generation and Omni 2 cohorts of the Framingham Heart Study (age = 46.4 ± 8.7; 53% women).

The omega-3 status was assessed by measuring the omega-3 index, i.e. the sum of EPA and DHA in red blood cells, which reflects long-term intake expressed as a percent of total fatty acids. Brain health was assessed by measuring brain structure, i.e. brain, total grey matter, and hippocampal and white matter hyperintensity volumes with MRI, and by measuring cognitive function, i.e. episodic memory, processing speed, executive function, and abstract reasoning with neuropsychological tests.

Regarding brain structure, higher DHA and EPA concentrations and omega-3 index were significantly associated with larger hippocampal volumes, and higher DHA concentrations and omega-3 index were significantly associated total grey and cortical grey matter volumes and lower white matter hyperintensities, which are white matter lesions. Regarding cognitive functions, higher DHA and EPA concentrations and omega-3 index were significantly associated with better performance in the Similarities test and decreased processing speed.

The authors then explored the interaction between the APOE status and omega-3 status on brain structure and cognitive function. APOE encodes for apolipoprotein E, a component of chylomicron and intermediate density lipoproteins involved in the clearance of cholesterol from circulating lipoproteins. APOE exists under three common isoforms, ε2, ε3, and ε4, depending on the genotype at two common SNPs, rs7412 and rs429358. It has been shown that APOE4 is the leading genetic risk factor for Alzheimer’s disease, with carriers of one copy of APOE4 (≈25% of the Caucasian population) exhibiting a 3-fold increased risk of developing Alzheimer’s disease while carriers of two copies (≈2% of the Caucasian population) exhibit an 8to 12-fold increased risk of developing Alzheimer’s disease (4). How APOE affects the brain had remained elusive but a recent publication in Nature has shed some light on its mechanism of action (5). APOE4 leads to a decreased processing of cholesterol by oligodendrocytes, which in turn decreases their production of myelin, a lipid-rich material that surrounds nerve cell axons, allowing their insulation, conduction of impulses, and metabolic support. Satizabal et al. compared the association of the omega-3 status with brain structure and cognitive function in ε4 carriers vs non-ε4 carriers. In non-ε4 carriers, higher DHA concentrations and omega-3 index were associated with larger hippocampal volumes while in ε4 carriers, higher DHA and EPA concentrations and omega-3 index were significantly associated with reduced white matter hyperintensities. Finally, in ε4 carriers, higher EPA concentrations were associated with better performance in the Similarities test.

Thus, this study shows that a higher red blood cell omega-3 concentration, namely of EPA and DHA, which reflects a higher omega-3 intake, is associated with better brain structure and cognitive function as early as midlife, i.e. before the onset of cognitive decline or Alzheimer’s disease. Moreover, this association is, at least partly, modulated by the APOE status, adding to the body of studies showing a differential omega-3 metabolism in the brain of ε4 carriers vs non-ε4 carriers, which could suggest that ε4 carriers require higher omega-3 delivery to the brain, and thus higher omega-3 intakes, to maintain brain health (6,7,8)


  1. 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 studies1–3. The American Journal of Clinical Nutrition 2015;103(2):330-40. doi: 10.3945/ajcn.115.124081.
  2. Andrieu S, Guyonnet S, Coley N, Cantet C, Bonnefoy M, Bordes S, Bories L, Cufi MN, Dantoine T, Dartigues JF, 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, placebo-controlled trial. Lancet Neurol 2017;16(5):377-89. doi: 10.1016/s1474-4422(17)30040-6.
  3. Satizabal CL, Himali JJ, Beiser AS, Ramachandran V, Melo van Lent D, Himali D, Aparicio HJ, Maillard P, DeCarli CS, Harris W, et al. Association of Red Blood Cell Omega-3 Fatty Acids With MRI Markers and Cognitive Function in Midlife: The Framingham Heart Study. Neurology 2022. doi: 10.1212/wnl.0000000000201296.
  4. Spinney L. Alzheimer’s disease: The forgetting gene. Nature 2014;510(7503):26-8. doi: 10.1038/510026a.
  5. Blanchard JW, Akay LA, Davila-Velderrain J, von Maydell D, Mathys H, Davidson SM, Effenberger A, Chen CY, Maner-Smith K, Hajjar I, et al. APOE4 impairs myelination via cholesterol dysregulation in oligodendrocytes. Nature 2022. doi: 10.1038/s41586-022-05439-w.
  6. Arellanes IC, Choe N, Solomon V, He X, Kavin B, Martinez AE, Kono N, Buennagel DP, Hazra N, Kim G, et al. Brain delivery of supplemental docosahexaenoic acid (DHA): A randomized placebo-controlled clinical trial. EBioMedicine 2020;59:102883. doi: 10.1016/j.ebiom.2020.102883.
  7. Tomaszewski N, He X, Solomon V, Lee M, Mack WJ, Quinn JF, Braskie MN, Yassine HN. Effect of APOE Genotype on Plasma Docosahexaenoic Acid (DHA), Eicosapentaenoic Acid, Arachidonic Acid, and Hippocampal Volume in the Alzheimer’s Disease Cooperative Study-Sponsored DHA Clinical Trial. J Alzheimers Dis 2020;74(3):975-90. doi: 10.3233/jad-191017.
  8. Yassine HN, Rawat V, Mack WJ, Quinn JF, Yurko-Mauro K, Bailey-Hall E, Aisen PS, Chui HC, Schneider LS. The effect of APOE genotype on the delivery of DHA to cerebrospinal fluid in Alzheimer’s disease. Alzheimers Res Ther 2016;8:25. doi: 10.1186/s13195-016-0194-x.

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