In this study we used an AD mouse model that carries both huAPP and huPS1 mutant transgenes and starts to develop amyloid deposits at the early age of two months. We backcrossed 5XFAD transgenic mice to the ApoE deficient background and we found a great reduction in amyloid load as expected. Although there was a significant reduction in amyloid deposition, 5XFAD/ApoE-/- mice developed amyloid plaques in the subiculum at the early age of four months. Also as it has been reported with other APP/PS1 transgenic mice, we observed a sex-specific effect on amyloid deposition with 5XFAD female mice developing amyloid deposits earlier compared to male littermates. As the prevalence of AD is higher in women it is noteworthy that a similar mechanism is likely to be present in the mice. The present study further implicates LDLR in the pathogenesis of AD suggesting LDLR as a potential regulator of the glial response in the development of the AD-like phenotype in an AD mouse model. Moreover we show that this effect can be independent of ApoE suggesting a novel mechanism. In conclusion, our results provide new evidence regarding the role of LDLR in the pathogenesis of Alzheimer‘s disease suggesting that LDLR could be a potential therapeutical target in AD. One-carbon metabolism comprises a set of reactions involving folate coenzymes and is critical for essential processes including DNA methylation, cell proliferation, and the synthesis of nucleic and amino acids. Insufficient folate or vitamin B12 intake, genetic variation, or drug interference can disrupt normal OCM function. OCM dysfunction is linked to severe health complications such as cancer, anemia and neural tube defects. Folate-mediated OCM also influences levels of the non-protein amino acid, homocysteine. Elevated homocysteine levels have been linked to an increased risk for neural tube defects. Recent studies have revealed widespread changes in gene expression under folate-deficient conditions. However, the underlying MG132 molecular mechanisms of these changes are poorly understood. Specifically, they associate with the RNA Induced Silencing Complex and guide it to target sites within mRNAs. Once bound to mRNA, RISC induces gene repression through a variety of mechanisms, including direct mRNA cleavage and translational inhibition. miRNAs have been implicated in a wide array of fundamental biological processes, such as development, lipid metabolism, response to environmental stress and innate immunity. Accordingly, mis-regulation of miRNA expression and/or activity has been linked to many diseases including various cancers and cardiovascular conditions, and is likely to underlie the molecular etiology of many other disorders. The role of miRNAs in the modulation of folate-mediated OCM has not been extensively investigated. However, initial studies suggest that folate influences miRNA expression.