Omega-3 fatty acids

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Research has shown that Omega-3s (also written referred to as omega-3 fatty acids, ω-3, or n-3), and especially DHA, are critical contributors to cell structure and function in the nervous system, and deficits in DHA are associated with cognitive decline during aging and in neurodegenerative disease. (Walter J. Lukiw, Nicolas G. Bazan, 2008, Pomponi M, et al., 2008))

A study of older adults at risk of late-onset Alzheimer's disease found that those who consumed more omega-3 fatty acids did better than their peers on tests of cognitive flexibility - the ability to efficiently switch between tasks - and had a bigger anterior cingulate cortex, a brain region known to contribute to cognitive flexibility. (Zamroziewicz, MK, et al., 2015)

While a review of observational and clinical trials that assessed supplementation with Omega-3 fatty acids such as docosahexaenoic acid (DHA) showed that it was not beneficial in symptomatic AD, several did show benefit in the pre-dementia stage of AD, suggesting supplementation may slow early memory decline in E4 carriers. (Yassine HN, et al., 2017)

We also know that in general population studies, Omega-3s have a positive effect in coronary heart disease (CHD) outcomes. (Dariush Mozaffarian, et al., 2013) ApoE4 carriers are at a higher risk of developing CHD.

Why Omega-3s are important for ApoE4s

  • Omega-3s come with a caveat. Higher Omega-3 levels appear to be beneficial for all genotypes, however, Dr. Bredesen generally warns males, with a 4/4 status and family history of stroke, to be cautious with fish oil supplementation. If you are a 4/4 male with a personal or male family history of stroke, talk to your doctor about using supplements (like fish oil) that thin the blood. If you have a male relative who suffered a stroke, be suspicious that it may have been Cerebral Amyloid Angiopathy (CAA.) There's a link between ApoE4 and CAA primarily in males. This is a very rare risk, but important to be aware of if you are taking ANY medication or supplement that thins the blood. (Mitsuru Shinohara, M, et al., 2016)
  • Evidence is mounting that E4 carriers actually need more Omega-3s than other APOE genotypes to reach similar Omega-3 blood levels, which are positively correlated with cognition. This paper (Chouinard-Watkins R, Plourde M, 2014) demonstrates that E4 carriers preferentially metabolize omega-3s suggesting E4s may actually need higher levels. Their novel hypothesis suggests that perturbed fatty acid metabolism, as opposed to elevated LDL-C, leads to both cognitive decline and coronary heart disease. The authors establish that E4 carriers preferentially metabolize DHA whereas the other APOE genotypes conserve it. (If you read this article, bear in mind that β-oxidation is NOT the same as lipid peroxidation, which is bad for you. β-oxidation (beta-oxidation) is the catabolic process in which fatty acids are used by the body as a source of energy. Lipid peroxidation refers to the oxidative degradation of lipids.)
  • Omega-3s can increase blood flow in the brain. Research compared brain images to the corresponding Omega-3 Index of participants and found a statistically significant correlation between higher blood flow and higher Omega-3 Index. In addition, they evaluated the neuropsychological functions of the subjects and found that omega-3 levels also correlated with various psychological feelings using a standardized test battery (WebNeuro). (Amen DG, et al., 2017) This might be of particular importance to E4s given that a reduction in blood flow is the first visible difference in E4 carrier's brains via imaging.


  • Eat more fish, such as salmon, sardines, mackerel and herring, but to be safe, reduce your consumption of fish that might have higher mercury loads, such as tuna or swordfish. Individuals who were E4 positive and consumed at least 1 seafood meal per week or had higher intakes of long-chainOmega-3s had less Alzheimer disease neuropathology compared with those who consumed lower amounts. (Morris MC, et al., 2016) With regards to mercury, they also found although seafood consumption was correlated with higher brain levels of mercury, these levels were not correlated with brain neuropathology. However, they do note that their "findings cannot be generalized to populations with higher seafood consumption or with high mercury exposure."
  • Take fish oil supplements. Eating fish alone might not be enough for E4 carriers, and supplementation might be necessary to raise Omega-3 index levels in the blood. (van de Rest O, et al., 2016) The two Omega-3s that are most brain-healthy are docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA). The MAPT study has found that 800 mg of DHA and 200 mg of EPA, as well as the multidomain intervention (exercise, nutrition, socialization) have the most benefit. (Vellas B, et al., 2014)
  • Watch your levels of B vitamins. Using data from the VITACOG study, these researchers showed when omega-3 fatty acid concentrations are low, B vitamin treatment has no effect on cognitive decline in MCI, but when omega-3 levels are in the upper normal range, B vitamins interact to slow cognitive decline. (Oulhaj A, et al., 2016)
  • Get an Omega-3 Index test done. Both Dr. Bredesen and Dr. Gundry suggest a minimum of 10% RBC EPA+DHA.

A deeper dive into the science

  • This study (Marta K. Zamroziewicz1, et al., 2015) is groundbreaking in that it examined omega-3 levels in an exclusively ε4+ data set. Rather than comparing the ε4+ population to the general population (which typically results in ε4 carriers demonstrating no benefit) researchers compared HIGH omega-3 levels (mean: 216.00 nmol/mL) vs. LOW omega-3 levels (mean: 102.30 nmol/mL) among ε4 carriers using both cognitive testing and brain imaging. These older adults at risk of late-onset Alzheimer's disease, who consumed more omega-3 fatty acids, did better than their peers on tests of cognitive flexibility, the ability to efficiently switch between tasks, and had a bigger anterior cingulate cortex, a brain region known to contribute to cognitive flexibility.
  • A recent paper (Matualatupauw JC, et al., 2016) reveals that the increased expression of interferon (IFN) signaling and cholesterol biosynthesis pathways might explain part of the association between APOE-ε4 and cardiovascular disease. Fish-oil supplementation may particularly benefit ε4+ individuals by decreasing expression of IFN signaling related genes.