Lp(a) Explained: Genetics, Risk, and What You Can Actually Do

Since you clicked on this video, I have to assume you've heard the term Lp. But to get everyone up to speed, Lp is a major risk factor for heart disease and the new hotness in the cardiology world. In particular, Lp is a causal risk factor for atherosclerosis, the buildup of plaque in the arteries of your heart. In fact, on a per-particle basis, Lp is thought to be at least 6 times as atherogenic—causing heart disease—as LDL cholesterol-containing particles. Now, two more things I want you to know about Lp off the bat. First, its levels are largely genetically determined—about 90% is genetic. And second, there aren't many medications or lifestyle treatments available today to modify Lp—although there are some, and we're going to talk about those. So the big question is, what do you do if you're genetically cursed like me, with high Lp? Well, by the end of this video, I promise you on my own heart health, because I do have endothelium in this game, you will have a much stronger understanding of Lp. You'll understand what it is, why it matters, and what you can do to reduce your risk of heart disease, especially if you're living with high Lp. Now, to give you a roadmap, this video will progress through 8 chapters. We're going to define Lp, talk about guidelines and measuring it and risk thresholds. We're going to talk about medications that are in development to lower Lp by as much as 99%. We're going to talk about how to reduce your risk of cardiovascular disease today if you have high Lp, how statins actually increase Lp and what this means, how saturated fat actually lowers Lp. We're going to talk about oxidized phospholipids on Lp and then nuanced notes. For the extra nerds out there, including ApoE genotype, hormone replacement therapy, and more. I want to brace you on this one for a whirlwind of information. This won't be easy. We're going to go through a lot, but I promise you, if you stick with this, when I'm done with you today, you will be armed with knowledge that will either intimidate your own cardiologist or make them swoon in nerdy appreciation. So with that, let's get to Chapter 1: defining Lp. What is it? Now, to understand Lp, you first need to understand a better-known lipoprotein particle, one you've probably heard of, the LDL particle. LDL particles are spheres that carry fat and cholesterol around in the bloodstream, and a core feature of both LDL particles and Lp particles is an ApoB lipoprotein that gives the particles structure and function. In fact, the broader class of particles floating around in your bloodstream that includes both LDL and Lp particles is called ApoB-associated lipoprotein particles. Makes sense, right? They contain ApoB. Now, here is the critical difference between LDL and Lp particles. Lp has a tail. That tail is an additional protein called apolipoprotein little a, which is coded in your DNA by the Lp gene. This apolipoprotein little a tail attaches to the ApoB protein with a bond. For the nerds, it's called a disulfide bridge. You don't really need to know that. But to quickly review what we just said, LDL particles and Lp particles are both particles containing ApoB, but Lp has the addition of an apolipoprotein tail attached to the ApoB. So the next question: what does the apolipoprotein tail on Lp do? Why am I talking about the tail at all? While the functions of the Lp tail aren't fully understood, it is known this protein tail does inhibit the breakdown of blood clots, effectively making your blood more clotty if you have high Lp. Specifically, Lp particles could, via the tail, attach to blood clots. These blood clots can block blood vessels, and Lp can promote their growth, leading to increased risk of cardiovascular disease. Why? Well, evolutionarily, this pro-clottiness feature could have helped younger individuals survive injury. And thus improve reproductive fitness. And it's also worth noting that LP developed during evolution twice, at least twice, independently in Old World monkeys and in guinea pigs. This is an example of convergent evolution, where in two different lineages, monkeys and guinea pigs, each developed the same adaptation, LP, to improve their reproductive fitness. Sadly, evolution doesn't always optimize, for healthspan and longevity per se. So the cost of evolving the Lp particle appears to be increased risk of heart disease later in life. A big picture general point here in biology is just because something was adaptive back then during evolution does not mean it's adaptive today. Anyway, it's not really helpful today to whine about how evolution screwed me, in more ways than one as we're going to find out. It's more important for you to understand that in this case, your genes, your your DNA strongly determine your Lp levels, and you can thank your parents for that. Concentrations of Lp are more than 90% genetically determined, with relatively minimal influence from lifestyle as compared to something like LDL. And most of this variation comes from the Lp gene, which codes for this tail, and something called Kringle repeats. Now, as a quick funny aside, if Kringle sounds like a pastry to you, it's because it is. It's a Danish variety of pretzel, and this isn't a coincidence. The kringle repeats in the apolipoprotein little a tail of Lp are named after that very Danish pretzel because they supposedly have similar structure, although I'm not really convinced. Anyway, that goofy aside over. In general, this is important, there is an inverse association between the number of kringle repeats, the size of the tail and Lp levels. So simply put, longer Lp tail equals lower Lp levels. Now, this is thought to be because the Lp particles with longer tails are more likely to be degraded in liver cells before being secreted into the bloodstream. If that didn't land, here's an analogy. Now, call me goofy, but I imagine it as if you had either a dense pack of Corgis, which have short tails, floating around in the bloodstream, or one or two German Shepherds with long tails running around in the bloodstream? Except in this comical case, the corgis, the Lp with the short tail, many corgis, they're the dangerous canines. Let me know if that was helpful, if it landed at all, or if you just like looking at corgi butts. Anyway, moving on to guidelines for measuring Lp and risk thresholds. Now that you understand what Lp is, Should you measure it? Yes! Guidelines from the United States, Europe, Canada, China, and India all suggest that measuring Lp at least once is important to include in your overall risk assessment. Now, what are the numbers you should look for on your lab report? What is good, and how high is too high? Well, first, it's worth noting that different reports use different units. You're either going to see nanomoles per liter or milligrams per deciliter. And just so you know how to convert between these, you can use this formula: Lp in nanomoles per liter equals Lp in milligrams per deciliter times 2.18 minus 3.83. Truth be told, the different units actually reflect slightly different measures, but this conversion will get you pretty close. Now, it's considered that people with Lp levels greater than 30 mg/dL are at a slightly increased risk. And those with Lp levels greater than 50 mg/dL are at clinically meaningful increased risk. And finally, those with Lp levels greater than 90 mg/dL are at severely increased risk. Now, in reality, the risk associated with higher Lp is continuous across the spectrum. But we humans like hard cut points, so there they are. And importantly, this risk appears to generalize across races and sexes. So in theory, the same Lp should confer similar risk in everyone. But as we will get to later in our chapters and in the nuanced notes, that's not actually the case. But first, 3, medications in development. While there are no medications currently available or prescribed to lower Lp, at least not for that indication, there are several in development with some really exciting results. Now, these medications work either by decreasing the expression of the Lp gene coding for that apolipoprotein little a tail, or by preventing the tail from attaching to ApoB. Most of these medications are of a class called small interfering RNAs and administered as injections. And there's also one pill that's in development that you can take by mouth, that's a small molecule inhibitor. Anyway, in double-blinded randomized controlled trials conducted in patients with elevated Lp, the interfering RNA injectables lowered Lp levels by as much as 99%, as shown in this graph below—the orange and gray lines. And the oral medication, which has the benefit of simply being oral—you can take it by mouth and you don't need to inject it—is slightly weaker, but it still appears pretty effective, lowering Lp up 85.8%. Now, as an important caveat, the results thus far are primarily looking at reducing Lp values on a lab sheet. This is different than monitoring for the actual clinical benefits, like fewer heart attacks and strokes. So, the biomedical community is still in the process of data collection. These medications aren't freely available. However, I do think the results are promising. That brings us to how to reduce your risk today. This is an important question to me personally, as I mentioned, my levels run in the high-risk category. This is not ideal, but rather than just curse my dad for bestowing me his short corgi-style Kringle repeats, I'm rather optimistic for one main reason. What I can control in terms of my risk is much greater than what I can't control. What I mean by this is I know my overall cardiac risk is determined by far, far more than a single lab value, be that LDL or Lp. I eat a healthy diet, I exercise, I have low insulin, low insulin resistance, low inflammation—we'll get to that in a minute—I have healthy and stable blood sugar, excellent blood pressure, and I'm working on my sleep and stress reduction routines. In fact, this is very much in line with the general thought process on how to handle patients with elevated Lp. The goal is to reduce other risk factors, including with healthy lifestyle practices, to reduce overall risk. Bear this in mind: if Lp acts as a risk multiplier of sorts, increasing your relative risk from some baseline, then if the baseline risk is lower, the absolute increase in risk is also lower. So let me give you an example, some simple math. If your risk of a heart attack over the next 10 years is 10%, a 50% relative increase in risk means your absolute risk increases to 15%. It increases by 5. But if your baseline risk of a heart attack over the next 10 years is only 1%, a 50% relative increase in risk means your absolute risk only increases by 0.5%. So same relative risk increase, +50%, but a tenfold lower absolute risk increase— absolute risk increase in heart attack or stroke. Makes sense? So, sorry to sound like a broken record to those who are longtime followers of me, but to sum it up in two words: context matters. Context always matters. And this is also a good point to remark on the interaction between Lp and inflammation. Data suggests that there's a synergistic relationship whereby people with higher Lp and chronic inflammation are at higher risk than those with high Lp but lower inflammation. Now, there are different ways to measure inflammation, including C-reactive protein, CRP, or high sensitivity C-reactive protein, hsCRP, and measuring levels of different inflammatory signaling molecules. One in particular is called interleukin-6, or IL-6. Now, the data on the CRP-Lp interaction are somewhat mixed, which may be because CRP is a rather nonspecific inflammatory marker. Still, on balance, lower CRP, lower hs-CRP is better—means less inflammation. But IL-6 is much more interesting to me in this case for a few reasons. First, IL-6 can activate the NLRP3 inflammasome and is an active participant in the causal cascade of atherosclerosis. Also, IL-6 can directly regulate the Lp gene, leading to increases in Lp levels. In fact, studies show that inhibition of IL-6 leads to 16— to 41% reductions in Lp. Now, whether this broadly translates into improved clinical outcomes remains to be seen, but it's an active area of investigation, with several ongoing trials, like the ZEUS randomized control trial, which is comparing an anti-IL-6 antibody to lower IL-6 activity to a placebo control. So we'll have to see what the results show. Moving on, speaking of medications, What about statins and Lp? Statins, as you probably know, are frontline therapy for lowering LDL cholesterol. But did you know they actually increase Lp? In a recent meta-analysis of randomized controlled trials, statins increased Lp by 10 to 20% on average. However, there is a high degree of individual variability. Some statin-treated patients see no increases in Lp., whereas others may see increases as high as 100 mg/dL. The mechanism behind this phenomenon is thought to be due to statins actually increasing the expression of the Lp gene, leading to more Lp. Indeed, when liver cells are treated with statins, Lp expression and apolipoprotein A levels—remember, that's the tail—increase in a dose-dependent manner. Now, does this mean statins are bad? No, not necessarily, I didn't say that. Like almost any medication, they come with pros and cons. Beyond LDL-lowering, statins can reduce inflammation, but they can also harm mitochondrial function, and to the point of this video, statins can increase Lp, leading to a presumed increase in Lp related residual risk. Now, typically, cardiologists advise that all patients with increased cardiovascular risk, irrespective of Lp levels, be treated with statins, as it's presumed that the benefits outweigh the risk for cardiovascular risk reduction. Now, I'll be blunt, that's not necessarily my shared opinion, at least not stated so simply, but I do think it's fair to report the majority expert opinion, so you know. For whatever expert consensus is actually worth to you these days. In any respect, you now have the information, and it's entirely up to you what you do with that. Moving on, does saturated fat lower Lp? The interaction between dietary patterns and macronutrients and Lp is an area of active investigation. And one interesting biological quirk, if you want to call it that, is that saturated fat appears to have a a discordant opposite effect on LDL particles and Lp particles, similar to what we discussed with statins. Higher saturated fat, lower carbohydrate diets tend to associate with or cause lower Lp. For example, in the GET READY trial with 166 African American individuals given either an American diet with 16% calories from saturated fat or a DASH diet with 6% calories from saturated fat in random order with a 1-week washout period, relative to the American diet, the DASH diet, which was much lower in saturated fat, did lower LDL cholesterol, but it increased Lp by 24%, or 11 mg/dL in absolute units. Furthermore, and this is important, those with higher baseline Lp saw larger increases in Lp when they were put on the low saturated fat diet. Increasing Lp by 16 mg/dL when they were put on the DASH diet. And similar results have been seen in other studies. Now, while more research is needed, this relationship whereby decreasing saturated fat increases Lp, and the effect is larger in people with high baseline Lp, speaks to the need for more individualized dietary treatments, especially in those with high Lp. Where it is possible that saturated fat reduction, especially in exchange for carbohydrates, could actually have a negative impact on cardiovascular health. All right, moving on. Oxidized phospholipids, or oxPLs, these are the cargo of Lp. So earlier we discussed how the tail on Lp can promote blood clots to potentially increase cardiovascular disease risk. But there are very likely other mechanisms at play. And one mechanism we need to talk about has to do with oxidized phospholipids, oxPLs, which are damaged polyunsaturated fats, damaged PUFAs, that promote inflammation and atherosclerosis. And just as a quick aside, don't confuse oxidized phospholipids, oxPLs, with oxidized LDL, oxLDL on your lab test. They're not the same marker. Just wanted to say that because it was potentially confusing. Anyway, the vast majority of oxidized phospholipids are carried on Lp particles. So you can kind of consider Lp reflective of a pool of harmful oxidized phospholipids. Interestingly, when you adjust for oxidized phospholipids, the relationship between Lp and major adverse cardiovascular events like heart attacks and strokes is actually substantially reduced. There's still likely a direct contribution of Lp, but this does raise the important and interesting question as to whether reducing oxidized phospholipids or neutralizing them could reduce risk associated with Lp without actually changing Lp levels, and whether those with high Lp but relatively low oxidized phospholipids are not actually at high risk as you'd think by looking at their Lp alone. Now, in general, interventions that lower oxidative stress and/or boost antioxidant capacity should in theory lower oxidized phospholipid levels. And because if I don't call out the seed oil elephant in the room, someone will, I'll just say it does remain an open question as to whether a diet enriched in high Omega-6 polyunsaturated fats, PUFAs, found in the group of oils commonly vilified today as seed oils, could, in theory, contribute to increased levels of oxidized phospholipids and risk associated with high oxidized phospholipids and high Lp. I make no direct claims, but I think it's a fair landscape for provocative speculation, with the big caveat that more research is desperately needed. Now, our final section: Nuance Notes on Lp. Before we close shop, I want to kind of rifle through some what I call nuance notes. First, size matters. I told you earlier that longer apoprotein tails on Lp lead to lower levels. We then focused on the level of Lp as a risk factor. However, even independent of Lp levels, shorter tails smaller Lp—remember the corgis—might be worse for your heart health than longer tails, larger Lps. This is an area of active investigation. And one reason I raise this nuance to note is that it appears there is some interaction between the size of Lp, the size of the tail, and response to various interventions. For example, niacin actually does lower Lp. However, the effect of niacin appears to be weaker when the apolipoprotein tail is shorter. Now, as another quick aside, I didn't mention niacin treatment before because it's generally not recommended due to the side effects and no proven benefits for improving cardiovascular outcomes. However, yes, niacin treatment has been shown to lower Lp by about 25%. But the real reason I raise this point is that there's a lot we still don't understand about how variations in Lp, including the size of the tail, impact risk, and how they might interact with lifestyle and/or medical interventions. It's quite complex. Alright, nuance note 2: postmenopausal women. Concentrations of Lp tend to increase about 17% after menopause. This is most likely due to decreases in estrogen. Which can impact Lp gene expression or Lp clearance. In fact, it's been known since before I was born that hormone replacement therapy can lower Lp in postmenopausal women. So there's some data for you. All right, nuance note 3: there are conditions in which Lp can change rapidly. For example, after a heart attack, Lp levels can plummet and then rise high above baseline, maybe 3 times higher than baseline, before coming back down to baseline about 4 weeks later. This is because Lp has another nature to it. It's what's called an acute phase reactant. The term isn't that important for our purposes. Just know there are some conditions where Lp levels can fluctuate massively and rapidly. Okay, nuance note 4: LDL cholesterol interpretation. And Lp. This one's a little bit confusing, but it's important. I differentiated earlier between LDL and Lp particles. Now, when you get your lab report and your lipid values, it typically reports an LDL-C or an LDL cholesterol. This is the cholesterol content within your LDL particles. However, reported LDL cholesterol typically also includes the cholesterol content of Lp particles. Or LP. And I raise this because if you have high Lp, your LDL cholesterol value on a lab report might be relatively inflated. This is just something to keep in mind when interpreting your own lipid panel. Alright, nuance note 5: APOE genotype influences Lp. You may have heard of the APOE gene, which codes for apolipoprotein E. There are 3 different flavors of this gene and its protein product: APOE2, APOE3, and APOE4. APOE4 is associated with an increased risk of Alzheimer's disease. And because each person carries 2 copies of this APOE gene, any given human being has 1 of 6 possible combinations: E22, E23, E33, E24, E34, or E44. The APOE3 variant is the most common, with APOE2 reducing risk and APOE4 increasing risk for Alzheimer's disease. And those with 2 copies of APOE4 are at the highest risk. And yeah, that's me too. Man, I'm really not rolling the genetic dice well today. But anyway, why am I bringing up APOE in this video about Lp? Because APOE plays a role not only in brain function but also in lipoprotein metabolism. It is an apolipoprotein after all. Specifically, ApoE4 appears to slow the clearance of lipoprotein particles like Lp, which may explain why carriers, especially ApoE44 individuals, tend to have higher Lp—about 65% higher Lp levels in ApoE44 versus ApoE22. As for whether high Lp directly harms the brain, the science is still fuzzy. Some early studies suggest lower Lp may correlate with better cognitive performance in older adults, but the evidence is weak and methodologically murky. What we do know is that vascular health is critical for brain health. So even if Lp isn't directly wrecking your neurons, it still may impact long-term cognitive function. By quietly undermining the plumbing that keeps your brain alive—the blood flow. So bottom line, if you've drawn the ApoE4 card—even if you've drawn it twice—and your Lp levels are high, it might be worth paying extra attention to your heart health—for the sake of your head. And remember, if that makes you feel doom and gloom, you are not alone. I drew an Lp of 165 nanomoles per liter and 2 copies of ApoE4. But my attitude is that knowing your genotype and biomarkers doesn't change reality, but it does give you the opportunity to modify your future. Knowledge is power, so wield it. Now, in conclusion, from genes to action. Where does this leave us? LP is primarily genetically determined, and thus largely a stubborn number that you won't easily change by hitting the gym or eating a healthy diet. But knowing your Lp isn't a sentence. It's a signal. A signal to act more intentionally, more proactively, and more intelligently about the things you can control. Remember, your Lp number may be set by your DNA, but destiny is shaped by your decisions. Medications are coming, even if they're not here yet, so lifestyle still matters. Context matters. Your overall risk is key. And the future of heart health is a mysterious landscape. I know we all want answers yesterday, but take heart in the fact that we are actively asking questions and making progress. And above all else, information is power when you use it smartly. If you've made it this far into this video, you are way ahead of the curve. Take a moment to appreciate yourself, and then talk to your doctor about measuring your Lp if you haven't already, assessing your full risk picture, and taking bold steps to protect the one heart you've got. Thanks for watching and caring so much about your health, as much as I care about mine. If this kind of deep dive into science and actionable health insights resonates with you, please, please, this is the only favor I'm asking, subscribe and share this video. This tells the algorithm you want more nuance and more metabolic health science. Stay curious. Hope you learned something valuable.