The underlying cause of many human cardiovascular diseases, including atherosclerosis and coronary heart disease, is a high level of low-density lipoprotein (LDL), known as “bad cholesterol.” Humans typically have about 70% to 80% of their circulating cholesterol in LDL, and only 20% to 30% in high-density lipoproteins (HDL), known as “good cholesterol.” By contrast, mice and rats have about 80% of their circulating cholesterol in HDL rather than LDL and, as a result, are very resilient to atherosclerosis and, by extension, may also be resilient to the vascular contributions to cognitive impairment and dementia. The reason mice and rats don’t have a human-like LDL:HDL ratio is that they are naturally deficient in an enzyme called cholesteryl ester transfer protein (CETP); i.e., they are essentially “CETP knockout” species. Importantly, low CETP activity in humans is associated with better cardiovascular health and reduced risk of AD. This project aims to improve the relevance of AD mouse model studies to the human condition by using commercially available CETP transgenic mice, which have a higher LDL:HDL ratio, to understand how LDL affects amyloid and APOE-mediated vascular pathologies in mice. Put simply, we plan to engineer mice to be more like humans in their lipid profiles, expecting that a higher LDL:HDL ratio will worsen both amyloid and vascular pathologies. If so, in the future we can test CETP inhibitors, currently in late-stage clinical trials for heart disease, to see whether these improve AD-relevant outcomes, and conduct additional studies to understand the mechanisms by which a high LDL:HDL ratio affects brain health.