#395 - Brain lipidology: understanding APOE, cholesterol homeostasis, Alzheimer's disease risk, and the effects of lipid-lowering therapies on brain health | Tom Dayspring, M.D.

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Tom Dayspring is a world-renowned lipidologist and one of the most thoughtful teachers in the field of lipid metabolism. In this episode, Tom returns to The Drive for a deep dive into the relationship between lipids and brain health, beginning with the fundamentals of cholesterol transport before exploring why the brain's cholesterol system operates almost entirely independently from the rest of the body. Tom examines the roles of apoB, apoA-I, and especially apoE in cholesterol homeostasis, discusses how APOE genotype influences Alzheimer's disease risk, and unpacks the complex links between cholesterol metabolism, amyloid, and tau pathology. He also reviews what is currently known—and still uncertain—about the effects of statins, ezetimibe, omega-3 fatty acids, and emerging CETP inhibitors on brain health and neurodegenerative disease risk. Although highly technical, this conversation provides an essential framework for understanding the nuanced relationship between lipid-lowering therapies, cardiovascular disease prevention, and neurodegenerative diseases in an area often clouded by misinformation.

We discuss:

• The fundamentals of cholesterol transport in the body, and how peripheral cholesterol metabolism differs from cholesterol handling in the brain [2:45];
• How cholesterol is transported through plasma and stored within cells, and why lowering LDL cholesterol does not deplete the body or brain of cholesterol [11:45];
• How apoB particles drive atherosclerosis, why lowering lipids matters, and the factors that influence individual cardiovascular risk [20:00];
• How the brain produces and transports its own cholesterol using apoE lipoproteins independently of circulating cholesterol and apoB-containing lipoproteins [29:00];
• How apoB structure influences LDL receptor binding and LDL clearance [39:00];
• How neurons acquire cholesterol from apoE-containing lipoproteins and why desmosterol serves as a unique marker of cholesterol synthesis in the brain [41:45];
• The difference between the APOE gene and the apoE protein, the major APOE genotypes found in humans, and how APOE4 influences Alzheimer's disease risk [48:45];
• HDL function beyond cholesterol: immune function, protein cargo, and communication with the brain [53:30];
• How APOE4-associated defects in brain cholesterol transport may promote Alzheimer's disease: amyloid production, neuronal cholesterol homeostasis, and cholesterol clearance [58:00];
• Statins and brain health: reviewing the evidence of the potential impact of statins on cognition and Alzheimer's disease risk [1:09:00];
• Desmosterol and 24S-hydroxycholesterol as biomarkers of brain cholesterol metabolism and statin effects [1:17:15];
• Possible cognitive benefits of ezetimibe beyond lowering apoB [1:19:30];
• EPA, DHA, and the evidence for omega-3 fatty acids in brain health [1:23:15];
• Obicetrapib: an emerging CETP inhibitor with potential implications for both cardiovascular and brain health [1:31:00]; and
• More.

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