The apolipoprotein E (APOE) E4 allele is one of the major genetic risk factors for late-onset Alzheimer’s disease (AD) and an important contributor to cerebrovascular (CV) dysfunction, which is now considered a major component of AD pathology. Recent advances in AD research suggest that E4 carriers have an age-dependent vulnerability in supplying glucose to the brain, which corresponds with lower glucose metabolism and precedes brain amyloid and tau pathologies. The CV system regulates glucose transport to the brain to support neuronal bioenergetics. With age, individuals with the E4 allele experience deficits in their ability to transport nutrients to the brain, which eventually, forces neurons to perform fatty acid (FA) metabolism. Fatty acid metabolism is harmful if performed in neurons as it can contribute to oxidative stress. The process of FA metabolism requires L-carnitine for transporting FA as acylcarnitines (CAR) into mitochondria (L-carnitine bioenergetics). The importance of this system in AD is highlighted by our recent study showing that L-carnitine-bioenergetic deficits are present in E4 carriers and correlate with CV pathologies in AD. Our animal studies herein show pathways that link glucose sensing with acetyl-CoA carboxylase (ACC) for L-carnitine- bioenergetics are altered in the cerebrovasculature of mice with targeted replacement of mouse APOE with human APOE4 (E4-TR) and AD mouse models with the human APOE4 isoform. We, therefore, hypothesize that E4 disrupts L-carnitine-bioenergetics within the CV cells, which corresponds with impaired transport of nutrients to the brain parenchyma. This increases the reliance on L-carnitine-bioenergetics within neurons and contributes to oxidative stress and inflammation in the brain. To test this hypothesis, we will first determine whether brain endothelial cells (BEC) or mural cells experience altered L-carnitine bioenergetics and determine the differential impact of APOE genotypes within both cells with age. We will then determine if boosting L-carnitine bioenergetics pathways by inhibiting ACC in BEC will help restore nutrient balance in the brain parenchyma. The proposed studies will provide novel insights into the role of ACC-mediated L-carnitine bioenergetics for developing therapeutic strategies specifically targeting E4 carriers, who experience a significantly higher cerebrovascular disease burden associated with AD pathogenesis.