Effects of APOE4 on omega-3 brain metabolism across the lifespan

Abstract

Omega-3 (n-3) polyunsaturated fatty acids (PUFAs), such as docosahexaenoic acid (DHA), have important roles in human nutrition and brain health by promoting neuronal functions, maintaining inflammatory homeostasis, and providing structural integrity. As Alzheimer's disease (AD) pathology progresses, DHA metabolism in the brain becomes dysregulated, the timing and extent of which may be influenced by the apolipoprotein E ε4 (APOE4) allele. Here, we discuss how maintaining adequate DHA intake early in life may slow the progression to AD dementia in cognitively normal individuals with APOE4, how recent advances in DHA brain imaging could offer insights leading to more personalized preventive strategies, and how alternative strategies targeting PUFA metabolism pathways may be more effective in mitigating disease progression in patients with existing AD dementia.

Keywords: APOE4; Alzheimer’s; DHA; fatty acids; imaging.

Figure 1.

APOE4 and brain lipid metabolism. In APOE4 carriers, lipid metabolism is differentially altered throughout three AD progression stages. We hypothesized that changes in brain lipids (such as lower DHA and greater cholesterol within lipid rafts of neuronal membranes) appear early and preceding amyloid deposition (Stage I), presenting an opportunity for increasing DHA intake to slow disease progression. As the disease advances to stages II and III, the brain shifts to PUFA oxidation for energy production, which accelerates tau-mediated injury and neurodegeneration. Most n-3 PUFA dietary and supplemental interventions were conducted in disease stages II and III and were not clinically effective. Figure created using BioRender.

Figure 2.

Cellular PUFA metabolism and APOE4 expression PUFAs are hydrolyzed and released from cellular membranes via PLA2 enzymes and are subsequently metabolized by COX, LOX, and sEH enzymes to generate pro-inflammatory and/or pro-resolving lipid mediators. cPLA2, which can be activated by Ca²⁺ influx and Aβ oligomers among other inflammatory stimuli, selectively hydrolyzes AA-containing phospholipids and promotes the production of inflammatory eicosanoids. PUFAs can also be synthesized from peroxisomes via β-oxidation and/or metabolized by FAO in the mitochondria to generate acetyl-CoA for ATP production. APOE4 induces the cPLA2 pathway to promote eicosanoid and PUFA oxidation. Figure created using BioRender.

Figure 3.

Can DHA supplementation delay APOE4 AD? Hypothetical models of brain DHA incorporation coefficient as a function of APOE4, age, and diet. Young cognitively healthy APOE4 carriers display higher rates of brain DHA incorporation coefficient (K*) uptake compared to non-carriers, suggesting greater brain reliance on peripheral DHA levels. We hypothesized that maintaining adequate DHA consumption early in life can decrease brain metabolic stress, as reflected by the lowering of the DHA brain incorporation coefficient obtained by PET imaging studies using 22-[¹⁸F]DHA. Aging and AD pathology decrease the function of the blood-brain barrier and brain DHA incorporation coefficient, reducing the effectiveness of these interventions later in life. Figure created using BioRender.

Figure 4.

cPLA2 activation in Alzheimer’s disease. Genetic (APOE4), environmental, and neuropathological factors enhance brain PUFA oxidation and cPLA2 activity, which can in turn accelerate the neuropathological hallmarks of Alzheimer’s disease. Figure created using BioRender.