#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.

**Peter Attia** (0:11)
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My guest this week is Dr. Tom Dayspring, who returned to the drive for another deep dive into lipidology. This time through the lens of the brain. Tom's been a frequent guest on the podcast and has had an extraordinary career. He's an extraordinary teacher, a mentor to me personally along with many others, and of course a colleague of mine for many years now in the practice. He's one of the most thoughtful lipidologists I know with a very remarkable ability to take complex physiology and make it not only clinically relevant, but understandable. In this conversation with Tom, we cover the fundamentals of cholesterol transport in the body, mostly just so that those who are coming to this for the first time or frankly, don't remember our earlier discussions on this, have the baseline. But then we really focus on the brain. We talk about why the brain's cholesterol system is almost entirely separate from the peripheral system, that is the rest of the body. We talk about the role of APO-B, which I've talked about a lot, and APO-A1, and specifically APO-E as it pertains to cholesterol. So we talk about how the APO-E genotype relates to Alzheimer's disease risk, which is something we prefer to a lot. But then the link between APO-E cholesterol, homeostasis, amyloid and TAL. What we know and what we don't know about the effects of statins, azetimibe, omega-3 fatty acids, and then the emerging CETP inhibitors on brain health. This is a technical conversation. I won't shield us from that, but it is an important one, especially for anyone trying to understand the relationship between lipid-lowering therapy, cardiovascular disease risk, and neurodegenerative disease. There's a lot of misinformation around this, and so unfortunately, you have to kind of get into the details if you want to understand these complex relationships. So without further delay, please enjoy my conversation with Dr. Tom Dayspring.
Hey, Tom. Great to be with you again, as always.

**Tom Dayspring** (2:52)
For sure, Peter. This has become a bit of a routine for us. We've done it, but I love the way we interact on this topic.

**Peter Attia** (3:00)
Today we're gonna talk about some different things. We're gonna really focus on a topic that's really become an enormous passion of yours, and your curiosity drives so much of your learning, and then by extension, our learning in the practice. So I want to kind of go on a journey with you into this idea of cholesterol in the brain.
It's obviously a very important topic for reasons that we'll get into, but I think before we do, it is worth making sure that everybody's starting from the same sort of knowledge base or singing from the same sheet of music, as some might say, as it pertains to lipids. So I know that you and I have discussed this in great detail elsewhere, and I realize that not everyone will have seen that, and even if they have, they might not recall. So let's start at the very beginning in a very short sort of five-minute version. Let's talk through the idea of cells in the body making cholesterol and how they have to move that cholesterol around the body in the periphery, just the sort of the nuts and bolts of it.

**Tom Dayspring** (4:01)
Yeah, as you've stated many times, cholesterol is essential for human life because it's used for making some critical things. But its most important function is it positions itself in the cell membranes in every cell in our body. And cell membranes regulate the integrity, what gets in, what gets out of cell. So evolution has given every cell in the body the power to de novo synthesize cholesterol. But a little bit. Now each cell needs a minor number of molecules or cell. But if it does that, we got great cell membranes and those cells are functioning happily or so.