2023 Alzheimer's Association Clinician Scientist Fellowship (AACSF)
Effect of Statins on APOE Levels, Lipid Metabolism, and Tau Pathology
Can certain cholesterol-lowering drugs help prevent dementia by reducing levels of a gene linked to dementia risk?
Michelle Rudman, M.D., Ph.D.
Washington University in St. Louis School of Medicine
St. Louis, MO - United States
Background
Nerve cells in the brain need cholesterol and other lipids (or fats) for energy and for maintaining their structures. As a result, the process by which fat is produced and transported to these cells is vital for proper cognition (brain function). One protein that helps carry fats throughout the body is ApoE. This protein is produced by the apolipoprotein E (APOE) gene, which comes in several variations, including APOE-e2, APOE-e3 and APOE-e4. Possessing the APOE-e4 variation is thought to increase the risk of Alzheimer’s in some populations. Studies, moreover, have found that individuals with APOE-e4 may experience alterations in lipid metabolism (or the breaking down on fats into energy). This process that may lead to abnormal lipid accumulation in the brain. It may also promote the clumping of dementia-related tau protein and, ultimately, nerve cell damage and memory loss in dementia. However, scientists remain uncertain exactly how different APOE variations impact lipid metabolism differently, and how these differences may be linked to dementia risk.
Initial studies found that cholesterol-lowering drugs called statins (including simvastatin) may significantly reduce APOE levels in mice. This finding supports the notion of a link between APOE and lipid metabolism in the brain, and it also suggest a role for statins as a potential strategy for preventing dementia in humans.
Research Plan
Dr. Michelle Rudman and colleagues will study statins, lipids and APOE in dementia using mice genetically engineered to develop tau in their brains with different APOE variations. First, they will administer different doses of simvastatin to mice with APOE-e4 to determine which dose level most efficiently reduces their APOE levels. They will then assess how the statin treatment impacts memory loss, tau clumping and other dementia-related brain changes in these animals. Next, they will examine how APOE-lowering statin treatment affects lipid metabolism in mice with different APOE variations (APOE-e2, APOE-e3 and APOEe4).
Impact
The results of this study could shed new light on the mechanisms underlying APOE-e4’s role in dementia risk. They could also lead to novel therapies that repurpose statins as dementia drugs.