Does APOE Genotype Modify the Relations Between Serum Lipid and Erythrocyte Omega-3 Fatty Acid Levels?

The effects of omega-3 treatment on lipid profiles in patients carrying an ε4 allele was examined in several previous studies, most from the University of Reading, UK. In the first, despite finding no significant effect of genotype on serum lipid responses to fish oil, the authors stated that, “In APOE4 carriers, the hypotriglyceridemic benefits [of fish oil] may be counteracted by a potential proatherogenic shift in the cholesterol profile” [7]. This conclusion was widely construed by many clinicians to mean that APOE4 carriers should not be given fish oil. A follow-up study reported no effect of genotype, but the dose of omega-3 fatty acids was rather low [9]. In the third study [8], normal volunteers (n = 20 for ε3/ε3 vs. n  = 18 for ε3/ε4) were given either 3.7 g/day of DHA or 3.3 g/day of EPA. The latter had no effect on LDL-C in either group, but the former increased LDL-C by 10 % from baseline in the ε4 carriers compared with a 4 % decrease in the reference group. Of note, apoB was not differentially affected by genotype nor was LDL-P raised by DHA [20]. A 2012 study including 88 subjects failed to confirm the adverse DHA effect [10]. There was no APOE genotype interaction for postprandial lipid responses while on a fish oil diet [21] nor did the authors find a genotype interaction for the effect of fish oil on LDL-C. Our findings, and those from the MESA investigators [12], are consistent with the majority view that the relationship between omega-3 fatty acid blood levels and LDL-C is not different in ε4 carriers relative to that in the common wild-type genotype.

Taking a wider view, it is well known that ε4 patients are at higher risk for CHD [5, 17] and for Alzheimer’s disease [22]. Even if the efficacy of fish oil supplements as treatments for CHD is in question [23, 24], several studies have shown that higher omega-3 fatty acid blood levels are associated with decreased risk for all-cause mortality [25–28] and dementia [29]. Direct consumption of EPA and DHA (whether from fish oil supplements or oily fish) is by far the most important determinant of the Omega-3 Index [30–33]. Their safety profile is strong [34], and thus, their risk/benefit ratio is favorable. Finally, because ε4 carriers may require higher doses of EPA + DHA to raise the Omega-3 Index (as suggested in some [35, 36] but not other [10] studies), patients carrying this allele may be the most likely to benefit from an increased omega-3 fatty acid intake.