Risks for developing cardiovascular‐based and Alzheimer’s neurodegeneration (ND) are strongly connected to Apolipoprotein E (ApoE) polymorphisms. There are three ApoE variants with differential impacts on ND risk, where variant 2 reduces and 4 increases risk relative to variant 3. These ApoE variants also impact cognition and memory in young healthy individuals, presumably through ApoE’s (primary) lipid transport function. Thus, a leading hypothesis is that the transport of lipids creates a metabolic bias in healthy subjects that sensitizes (or protects) the brains of these subjects to physiological stresses which leads to ND. In support of this hypothesis, lifestyle choices including exercise and diet, which shift metabolic patterns, modify the risk of ND as much as genetic predisposition. The interplay of genetic and environmental risk factors indicate that the preexisting metabolic condition of the brain is a key initiating variable, and that interceding in this metabolic bias represents a viable method for preventing disease. Unanswered questions, however, include which metabolic pathways are most impacted by the ApoE polymorphism, and how does age exaggerate the metabolic condition to promote ND. Modified lipid metabolism is a unifying variable between long‐term inflammation, reduced cellular repair and modified energy availability which all promote ND. We have developed methods to monitor the turnover of lipids and proteins in vivo. Coupling this with mass spectrometric (MS) imaging, we can see spatially distinct in vivo metabolic regulation across the brain. A systems‐level investigation, in which the fluxes of many lipids and proteins are simultaneously measured, may be the most sensitive approach to monitor ApoE‐dependent changes in regulation of metabolic networks. It is probable that the ApoE isoforms bias lipid delivery to different regions of the brain. This bias creates regional long‐term shifts in metabolism, which change the risk for damage due to stress. Comparison of changes in brain metabolism between ApoE2, ApoE3, or E4 mouse models and the age‐dependent changes for each genotype will help to identify metabolic patterns that protect the brain from accumulation of damage. The overall objective of this proposal is to monitor regional changes in metabolic pathway control and identify how ApoE shifts metabolic flux. The central hypothesis is that ApoE2 biases metabolism to a pattern that protects metabolic control or regulation, while ApoE4 biases lipid metabolism in the opposite direction resulting in more rapid age‐related loss of metabolic control.