Despite the observed association of the omega-3s docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) intake or blood levels with Alzheimer’ disease (AD) incidence and cognitive outcomes, omega-3 clinical trials have largely been negative. Carrying the APOE4 allele is the strongest genetic risk factor for AD. Therefore, identifying how APOE4 affects the response to omega-3 supplementation can help refine newer and more personalized trials. DHA supplementation increases EPA levels and EPA has strong anti-inflammatory effects. The ratio of EPA to arachidonic acid (EPA/AA) is a marker of tissue inflammation.
We examined the effect of APOE4 on the change in plasma and cerebrospinal fluid (CSF) EPA/AA in two different clinical trials: the ADCS-sponsored DHA trial in patients with mild AD (n=402), and the Brain DHA Delivery Pilot trial in cognitively normal participants (n=33). In both trials, participants were randomized to high doses of algal DHA (2 grams per day). A subset of the ADCS-sponsored study underwent MRIs for measurement of hippocampal volumes (n=86).
Plasma EPA/AA was significantly lower in APOE4 carriers compared to non-carriers after high dose DHA supplementation in both trials. CSF EPA/AA differed by APOE4 genotype in the Brain DHA Delivery Pilot, with APOE4 non-carriers having two times greater increase in CSF EPA/AA than APOE4 carriers (30 vs. 14% increase, p=0.001) after supplementation. Greater increase in plasma EPA/AA was positively correlated with less decline in the right hippocampal volume (r=0.31, p=0.03) with APOE4 modifying this association (interaction p value, p=0.01, Figure 1).
APOE4 appears to limit the conversion of DHA to EPA after DHA supplementation by promoting EPA’s mitochondrial oxidation. These changes start before the onset of dementia. We propose that the plasma EPA/AA can serve as a biomarker for DHA supplementation efficacy. Prospective validation of this biomarker can guide the development of more personalized omega-3 interventions designed to reduce the increased AD risk with APOE4.