s supply neurons through a dedicated internal transport system - APOE genotype and Alzheimer's disease risk: how the apoE4 isoform disrupts cholesterol delivery to neurons, why that disruption connects to amyloid and tau pathology, and what the non-linear risk increase across genotypes means in practice - Lipid-lowering therapies and the brain: what the evidence shows about statins, ezetimibe, and omega-3 fatty acids when it comes to cognition, neurodegeneration, and brain cholesterol metabolism - Obicetrapib and Alzheimer's disease risk: early data from the BROADWAY trial showing promising movement in - Alzheimer's biomarkers including p-tau, the mechanism by which CETP inhibition may increase apoA-I entry into the brain, and why the effect appears especially pronounced in APOE4 carriers - Much more Listen (Ep. # 395) to the full episode on my website or your favorite podcast player.

hy we don't have complete and total homogeneity of risk factor and disease? And when we confine it to this disease, I mean, we don't have it for any disease, but what do you think is the best explanation for a disease in which we so well understand the physiologic steps? Sure. Well, as I mentioned, if cholesterol gets in your artery wall, you have the disease and it's the ApoB particles bringing them in. But that is not the only etiologic reason why one would have atherosclerosis. There are a number of other factors that go into play and it's the rest of your health. Your metabolic health is a major concern. If you are insulin resistant up to type 2 diabetes, you have chronic inflammation in the body. You have endothelial cell damage in the body. So it's easier in those people for these particles to get in earlier in life and generate in plaque. We should make the point that this ApoB entry into the artery wall is an incredibly slow process. It takes decades to develop. And this is why the concept now is not only lower is better, but the longer you keep things low with ApoB is better. So your blood pressure would be a factor. Your smoking, as you said, if you have some autoimmune disease that's contributing to inflammation. We know people who have chronic inflammation have increased atherosclerosis. Collagen diseases, rheumatoid arthritis, they have lifelong inflammatory factors going on in other abnormalities that weaken the arterial defense against atherosclerosis. Oxidative processes is a big part of atherogenesis. So if that is going on in the body, but sometimes we do see, like you said, great grandma who smoked all her life and has high LDL cholesterol and why no plaque? And there are forces at play that we just do not understand. There's other protective whatever going on in their body that we have not been able to identify even genetically or we're testing this test. Oh, they got some elevation of molecule Z. It's protecting them. Something's protecting them. Something's going on. And one day we'll ascertain that, you know, as the polygenic risk scores come into, if we do them early in life, it can sort of predict who is going to make it to 80. We never have a heart attack and who is not because they're looking at a multitude of genetic things that you are never looking at one at a time in an individual patient. So look, genes control everything. They are genetically blessed. But important thing to make is don't ever think because your LDL cholesterol is 200 that I'm one of them because there's no way to know that. Why play Russian roulette and think it's not going to bother me when for the vast majority of people it does create havoc and pathology?