The risk of Alzheimer's disease is increased for carriers of apoE4 (E4) or the PPAR-alpha L162V polymorphism (L162V), but it is decreased in fish and seafood consumers. The link between high fish intake and reduced risk of cognitive decline in the elderly appears not to hold in carriers of E4, possibly because better cognition is linked to EPA+DHA in the blood, but only in non-carriers of E4. As yet, no such studies exist in carriers of L162V. Our objective was to determine whether the plasma fatty acid response to a dietary supplement of EPA+DHA was altered in carriers of L162V and/or E4. This was an add-on project; in the original study, men were selected based on whether or not they were carriers of L162V (n 14 per group). E4 status was determined afterwards. All subjects received an EPA+DHA supplement for 6 weeks. L162V polymorphism did not interact with the supplement in a way to alter EPA and DHA incorporation into plasma lipids. However, when the groups were separated based on the presence of E4, baseline EPA and DHA in plasma TAG were 67 and 60 % higher, respectively, in E4 carriers. After the supplementation, there were significant gene x diet interactions in which only non-carriers had increased EPA and DHA in plasma NEFA and TAG, respectively.