APOE4 attenuates the response to DHA supplementation in patients with Alzheimer’s disease by Victoria Solomon

Apolipoprotein E4 (APOE4) gene increases the risk of developing Alzheimer’s disease (AD). Docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) are both omega-3 fatty acids, found largely in seafood and fish oil, that can help protect the brain from inflammation and AD. Arachidonic acid (AA), on the other hand, is an omega-6 fatty acid found in chicken and eggs that has been associated with brain inflammation and cognitive decline.

In the Alzheimer’s Disease Cooperative Study-sponsored DHA clinical trial, researchers observed that after giving older individuals diagnosed with mild AD DHA supplementation in the form of omega-3 gels for 18 months only APOE4 non-carriers showed improvement in cognition and memory, while those carrying the APOE4 gene did not benefit from DHA supplementation.

In our study we hoped to understand how APOE4 affected the changes in the levels of DHA, EPA, and AA in blood and cerebrospinal fluid as well as change in hippocampal size in this study.

We found that participants carrying two APOE4 genes (APOE ɛ4/ɛ4) treated with DHA supplements were less able to increase DHA levels in their blood than APOE4 non-carriers. We hypothesize that the APOE4 gene may change how DHA is metabolized in the body, ultimately suppressing the benefits of DHA supplementation and making it harder for DHA to get to the brain in patients with AD.

In this illustration, (A) we show how competition between esterified DHA and AA in triglycerides (TG) and phospholipids (PL) from circulatory lipoproteins into the sn-2 position of phospholipids of the membrane bilayer by sPLA2 and cPLA2. Due to greater intake of AA in the western diet, more AA is incorporated into the membrane bilayer.  B) Ingestion of dietary DHA after supplementation remodels membrane phospholipid bilayer by the activities of cPLA2 and the acyl-coA transferanse. In addition DHA is able to retroconvert into EPA. EPA also incorporated into the bilayer. C) Preferential mitochondrial oxidation of DHA by the APOE4 genotype is associated with greater expression of mitochondrial CPT1, providing a mechanism for the lower incorporation of DHA into the membrane bilayer

Read our publication in The Journal of Alzheimer’s Disease here: