Omega-3 fatty acids

Introduction

Several lines of reasoning have led to the hypothesis that consumption of some, or any omega-3 fatty acids (DHA and EPA, found primarily in fish, and ALA, found in plants) will reduce the risk of dementia and can even improve cognition in youth and in those with cognitive decline.

We do know that in general population studies, omega-3s have a positive effect in coronary heart disease outcomes.

• "Circulating individual and total n3-PUFA are associated with lower total mortality, especially CHD death, in older adults. (Dariush Mozaffarian, et al., 2013)

Why Omega-3s are important for ApoE4s

This one comes with a caveat. It appears to be beneficial for all genotypes, except for male E4/E4 carriers with a family history of stroke.

Evidence is mounting that E4 carriers need more Omega-3s than other APOE genotypes to reach similar Omega-3 index levels, which are positively correlated with cognition. This paper Raphaël Chouinard-Watkins and Mélanie Plourde, 2014) demonstrates that E4 carriers preferentially metabolize omega-3s suggesting this population may actually need higher levels. (If you read this, bear in mind that β-oxidation is NOT the same as lipid peroxidation. 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.)

This 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. (Raphaël Chouinard-Watkins and Mélanie Plourde. 2014)

The Science

Researchers have long suspected that the reason DHA has not been effective in providing cognitive benefit to ε4 carriers is that the negative consequences of DHA consumption (DHA oxidation) overwhelm potential benefits, and that consumption of sufficient antioxidants along with the DHA, or, alternatively, consuming it in a natural form, where it would be less subject to oxidation, would permit it to be beneficial for ε4 carriers. For a summary, see "Omega-3s, ApoE Genotype and Cognitive Decline". This theory has not been tested however, and the epidemiological evidence offered in support of the theory is mostly from societies that consume the omega-3 fatty acid found in plant-based diets, ALA (which, itself, may help ε4 carriers, but more research is needed). Indeed, recent evidence has demonstrated an alternative explanation for the differential effects of Omega-3s in ε4+ individuals via disrupted fatty acid metabolism.

This study Anterior cingulate cortex mediates the relationship between O3PUFAs and executive functions in APOE e4 carriers is groundbreaking in that it examined omega-3 levels in an exclusively ε4+ data set. Rather than comparing theε4+ 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.

Additionally, the ongoing MAPT trial in France, has found that ε4+ carriers benefitted more from omega-3/DHA supplementation, than any other APOE genotype when it was combined with other strategies: diet, exercise, cognitive & social stimulation. See the press release here.

A recent paper, E genotype status affects habitual human blood mononuclear cell gene expression and its response to fish oil intervention 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

Other researchers, concerned that the levels of mercury in fish could negate any potential neuroprotective benefits, tested that theory in their paper Association of Seafood Consumption, Brain Mercury Level, and APOE ε4 Status With Brain Neuropathology in Older Adults. Tthey did find that eating a moderate amount of seafood was tied to higher levels of mercury in the brain, but these higher levels weren't associated with more Alzheimer's neurology. Interestingly, the cognitive benefits of having one seafood meal per week was ONLY found in ε4+ individuals on multiple measures of Alzheimer's disease.

• Lower density of neuritic plaques (β= -0.69 score units)
• Less severe and widespread neurofibrillary tangles (β= -0.77 score units)
• Lower neuropathologically defined Alzheimer's disease (β= -0.53 score units)

These more recent studies are moving away from the conclusions of earlier work that reported ε4 carriers are unable to benefit from omega-3 fatty acids. As researchers work towards better understanding how omega-3 impacts the APOE-e4 gene, it might be wise to ensure maintenance of adequate levels.