Brain Health Q&A: ApoB, APOE2, pTau217 & More

What's the optimal ApoB level to reduce Alzheimer’s risk? Is lifestyle or genetics more important? And what does a pTau217 result actually mean for your brain health?

In this Brain Health Q&A, I answer your questions about ApoB, APOE2, dementia prevention, blood-based biomarkers, and what the science actually says right now.

Missed the first video? Check it out here: https://youtu.be/y8vkJE_Zy7A

Topics include:
• How low I think ApoB should ideally be for brain health (and what matters more!)
• How to think about lifestyle vs genetic risk like APOE4
• What current guidelines recommend for pTau217 and its limitations
• What I’d personally focus on for long-term brain protection (and teasers for our upcoming videos in the series)

As a vascular surgeon specializing in cardiometabolic prevention, I spent years treating the downstream consequences of vascular disease after the damage was already done. Brain health is no different. Prevention matters most before symptoms start.

The brain is not magically separate from the rest of the body. Blood vessels, inflammation, metabolic health, sleep, exercise, and genetics all interact over decades. So let’s talk about how to think about that risk honestly — and practically.

👇 Drop your questions in the comments for the next Q&A.

Sign up for more information on my own practice here: https://corsighthealth.com/

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___________________________
🧬 About Dr. Lily Johnston
  
Dr. Johnston is a double board-certified vascular and general surgeon in San Diego, specializing in metabolic and cardiovascular prevention. She’s the founder of CorSight Health and a passionate advocate for reimagining how medicine approaches chronic disease.
  
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Transcript

SPEAKER_00 0:00

I'm back with more comment responses. Hey guys, Dr. Lily Johnston. I am a board certified vascular surgeon if you're new here, but I specialize in cardiometabolic prevention. So hopefully you never need me as a surgeon. Last weekend we talked about the role of APOE4, the gene and the protein in brain health, specifically the risk for Alzheimer's dementia. You guys came back with some great questions. Let's get into them. Thomas Archer says, I look forward to your next discussion. Specifically, do you recommend DAJA supplementation for ApoE4 carriers? And if so, from what source? Thanks, Thomas. This is a great question. And even though I promised we were going to do supplements in part two of the APOE4 series coming up soon, it's actually going to be its own special part three because part two got so long with so many other things that we can do to mitigate our risk for dementia, especially from Ape OE4, that supplements, which I really think of as kind of the last 5% of what we can do to help reduce our risk, is going to be its own separate part three. So stay tuned for that. We will get into it, I promise. Our next question comes from at Live Physiology. This video covers such important aspects of the genes versus the risks. Especially important is the part about ApoE4 in Lagos versus Atlanta. What role do other factors besides genetics play in disease and prevention? Great video. Thank you, Live Physiology. There are so many things that contribute to potential risk for the development of dementia generally and Alzheimer's more specifically. If you are interested in this, I cannot wait for you to come watch part two. We are going to go through all of this in really excruciating detail. But the Lancet Commission outlines 14 different potentially preventable sources of risk for the onset of dementia. And it ranges everything from education to traumatic brain injury, hearing and vision loss, nutrition, movement, specifically the risk for obesity, for example, and diabetes. There are so many different factors. And even though that can be a little bit overwhelming to think about, and some of them are truly more in our control than others, because most of us don't have a huge amount of choice about how much early childhood education we get. And most people don't sign up for their traumatic brain injuries. So I get that some of that is quasi-modifiable. However, there are a large number of these factors that are things that you and I can pay attention to and really impact in our day-to-day lives, including the things we put in our mouth every day, the decisions we make about intentional movement and our sleep and our stress. So I am really excited to go through this with you in detail in part two. I can't wait for you to stick around for that. And user Candace24 asks, I've been on Rosuvastatin 5 milligrams for the last one and a half years due to elevated LP little A of 77 milligrams per deciliter. By the way, if you haven't seen the LP little A series, please go check that out. And I just tested my ApoB. It's 70 milligrams per deciliter, LDL is 59 milligrams per deciliter, and I have a copy of APOE4. So I'd like to be more aggressive to optimize my numbers. My cardiologist is happy with my numbers. So before I discuss it again with her, I'd appreciate your thoughts. Given my genetic risk factors, should I add a ZMIB or should I increase my statin? Or are my numbers optimal and there's no need to change? Thanks, Candace, for a great question. And the there's two answers here. The first answer about truly just the lipid APOB numbers is nobody knows. There seems to be a linear increase in risk for the development of dementia with increasing LDLC. That's what they tested, not APOB, but since yours are fairly concordant, we can use that as a proxy. However, what I don't know is how low is low enough to mitigate that risk overall. You know, you're in the quote unquote normal range, but what's optimal? The short answer is data don't really tell us what will be optimal or how to get it there, because again, what is circulating in your periphery, meaning in the blood that is sampled when we get a lab test, is not totally reflective of what's going on in the brain, especially when APOE4 is involved. We just don't know what's happening with the lipid trafficking on the other side of your blood-brain barrier. So the short answer is we don't know. In general, for patients, if my thoughts are we need additional APOB lowering, my general preference is to use azetomybe and statin rather than go up on statin dosing, which leads me to the second part of this answer, which is if we're gonna broaden your question just a little bit and talk about overall optimal numbers and values, my next question actually is much less about your lipids, because again, you're in a pretty good place. Could it be lower? Sure. Will it be helpful? I am not sure. But what I do know is there are more numbers that are important. So what's your blood pressure? What's your fasting insulin? What's your HOMA IR? Like these are actually the other numbers that I think in the grand scheme of your risk for dementia might be way more impactful than another 10 milligrams per deciliter of LDLC lowering or something like that. I'm pleased to see that you are not somebody who had an increase in LP little A on your statin therapy. That's excellent. And again, the real answer to your question is to like step back and look at the whole big picture. And my hope is that, you know, we're nitpicking on this last little bit of APOB because everything else is all in order. But I would say, you know, if you were my patient, what I would offer would be the opportunity to check on everything else going on and make sure that there's no low-hanging fruit elsewhere in the risk profile that could be addressed. So thanks for that question. Hope that helps. This next one plays to my surgical strengths. So JPAT asks, I have a related cholesterol plaque question. In 1998, I had an occluded carotid dissection with a stroke. Yikes. And amazingly, over the years, it's opened back up to 100%. The only obvious hard plaque I have in my body is on the carotid bulb. Will there be any vascular weakness in the dissected carotid, the internal carotid artery? So this is a cool question, and I don't know is the short answer. The textbook would tell you that any artery that has had a dissection. So wait, sorry, let me step back. Dissection, if you've not been here for the previous conversations we've had, is a peeling away of one layer of the three in the artery wall. So arteries have three layers: the intima, the media, and the adventitia from inner to outer. And a dissection is when the intima separates from the media and the adventitia, and it creates this flap that floats around on the inside of the artery wall. And if it flaps to the other side, it creates this blocked false channel called the false lumen. And because it doesn't go anywhere, the blood becomes static and stagnant and it tends to clot off or occlude. And as unfortunately, JP experienced that can cause a stroke in every other vascular bed. It can cause infarction or poor circulation, loss of blood flow. So it's a big deal. The other thing you would naturally imagine is that now that you've peeled away one of the three layers of that artery wall, the artery itself might become weakened now that it doesn't have one of its three layers. And when this happens in the aorta, the big blood vessel that leaves the heart and delivers blood to the rest of the body, certainly we can see over time that the aorta begins to have what we call aneurysmal degeneration, which just means it gets bigger and bigger over the years as the pressure from the heart and the circulating system pushes on the wall and the wall has been weakened. That tends to be less problematic in other vessels like the carotid or the celiac or the SMA, the superior mesenteric artery. Celiac and SMA are two of the big blood vessels that bring blood flow to your intestines in the abdomen. But we do still monitor them over time for any signs that they're growing or becoming dilated. And that would suggest that there is weakness in the wall of the artery. After a while, what's a while? Years, we don't really know. If there's no growth, we sort of believe that things have stabilized over time and probably will not grow further beyond that point. And whether or not we can still see that dissection flap or that one layer of the artery wall flapping around in there also would suggest that perhaps there's more likely to be weakness, but we don't know for sure. JP, what I would say is I think if your artery looks completely normal again, right? There's no flap, there's no enlargement, there's no plaque, and it's been several years since your event, I wouldn't I think it's going to be more and more stable over time, not weaker and weaker over time. But that's a best guess. Okay? Hope that helps. And next is a question from William Henry. You left me hanging. Sorry. Uh I am ApoE2 slash three. And in the beginning you said ApoE2 has its own issues, but did not expand on it much. You did say that people with ApoE2 are dumber. Did I say that? Because I really didn't mean to say that. I'm pretty sure I did not say that. But uh anyway, they're not dumber. ApoE2 is one of those three right isoforms of the ApoE protein. And what I meant when I said ApoE2 can have its own issues is really mostly associated with people who are a 2-2 genotype. And about 5 to 10% of those people, which is by the way, uh a very small percentage of the population in general, anyway, about five to ten percent of ApoE22 carriers will have something called type 3 uh hyperlipoprotonemia or hypobeta lipoprotonemia. This is a problem with clearing triglycerides and very large density lipoprotein or VLDL remnants from circulation because the ApoE2 isoform of the protein does not bind the LDL receptor quite as well in the liver. And so we have trouble clearing our chylomicrons and our remnant particles. These remnant particles are a type of circulating lipoprotein, cholesterol, right? They are probably a little bit more prone to causing plaque to form in arteries, or they are more athrogenic, is the other way that I sometimes say that. And ultimately, in patients who have dysbetalipoproteemia, this problem clearing remnant particles, there is like a pretty significant increase in peripheral arterial disease or PAD. And that is something that as a vascular surgeon, I actually treat fairly frequently. And most of it does not come from this um type 3 hypobeta lipoproteinemia, but it does come from all kinds of plaque forming. So what's interesting though is why would a particle that, or a protein, excuse me, that does not clear remnant particles from circulation well, how would that be protective in the brain, right? Because I told you that APOE2 is protective typically with um with respect to Alzheimer's dementia risk compared to our baseline ApoE33 genotype. So like the fours have increased risk, but the twos tend to have lower risk. So why did like how does that compute? And I actually really struggled with this. And the problem is that in the brain, the ApoE2 proteins actually have more lipids associated with them, more lipoproteins that are being trafficked, and they improve clearance of amyloid beta, which is paradoxical because that's not what we see in the periphery. The other thing that's cool about the two twos or about the ApoE2 protein in the brain is that ApoE2 can form these interesting disulfide bridges, which is just a protein configuration, but it makes the lipoproteins that are attached less likely to be oxidized or peroxidation reactions. So we protect the brain from oxidative stress related to these lipoproteins if we have that ApoE2 protein isoform. So, William, it is not actually bad news for you. You don't have a 2-2, so you don't have really any increased risk for the bad lipoprotein circulation problem. By the way, that 5 to 10% of people, we don't know who's going to have it. It seems to be what we call a double hit hypothesis, meaning you have the ApoE2 genes, but something else probably also contributes to setting off this dysbeta-lipoproteinemia problem. And we don't totally know what that is, but I would suspect any touch of insulin resistance might really exacerbate that or at least increase the number of remnants that have to be cleared. So controlling your insulin is always a correct answer for this. And um I don't think you're dumber. But thanks for the great question, and I hope that helped. And LLS66 says, wondering about the ability to test for brain inflammation available to the public, direct or indirect. That is a great question. I don't think, to my knowledge, that there is any test that specifically reflects brain inflammation. We have options to test general inflammation like high sensitivity C reactive protein, um, ESR, erythrocyte sedimentation rate is another one that is sometimes used, although I tend not to use it in my practice because ESR is not quite as tightly correlated with cardiovascular inflammation. And then if we're going to get real specific about blood vessels, we have LPPLA2, which is a vascular-specific marker of inflammation related to the white blood cells that are actually forming plaque in our artery walls. And that's a good one. As for the brain, I am not aware of any brain-specific inflammatory markers that we can test. Perhaps some of the imaging tools might be able to account for that. But right now, the only good serum-based marker that I know of that helps us understand much about risk for Alzheimer's dementia is the PTAW 217. And there are some others like GFAB and NFL that have also been used. But right now, the most likely to emerge for clinical use is going to be the PTAO 217. And I want to take you through what open evidence says is the current best practice for this because many of you are going to want to know whether this is something you should have checked. So here is our open evidence report for what current clinical guidelines are for the use of PTau 217 and other blood-based biomarkers for the detection of Alzheimer's dementia. So it says the American Academy of Family Physicians recommends that blood biomarker testing, particularly plasma PTAu 217, be used in primary care patients for those with abnormal cognitive assessments. So that's going to be something like a mini mental status exam or a MOCA assessment, and in whom other causes of cognitive impairment have been ruled out and who may be candidates for disease modifying therapies or other Alzheimer's dementia specific treatments. The AAFP explicitly advises against BBM testing in cognitively unimpaired, meaning normal individuals, as it can introduce diagnostic uncertainty. What does this mean? If you have cognitive impairment on a standardized test, then the blood marker P tau 217 may be helpful to understand whether there's been an accumulation of amyloid in your brain. If you are cognitively normal, we are currently not recommending routine testing outside of a clinical trial or study. This is only one of several available biomarkers. So we also have plasma amyloid beta 42 and 40. That usually comes as a ratio. Both of these, PTau and amyloid beta 4240, are identified as the most predictive biomarkers for assessing amyloid and tau burden in the brain. Of them, PTau 217 has demonstrated the highest accuracy in predicting amyloid PET positivity. So this means if you're gonna go get additional imaging testing, you might get a PET scan or positron emission tomography. This is an active form of neuroimaging or brain imaging, where we are looking at the uptake of glucose typically in certain regions of your brain. And sometimes we can use that to tell whether there is an abnormal amyloid signal in patients who are trying to get a diagnosis for Alzheimer's. So PTAW 217, highest correlation with P-based imaging. And our key considerations: there are a couple of different labs or um vendors that are offering PTAW 217 testing. The performance of these biomarkers varies by different labs, and the cutoffs are not interchangeable. So your PTAu 217 level has to be interpreted with the reference range given by the lab that did your test. You can't necessarily compare that to my PTAW 217 level that was done by a different lab that has a totally different cutoff. It's not like LDLC where these are sort of normed across all labs internationally. Okay. And this is what we have today, but we expect more biomarkers to evolve over time as we get smarter. And these blood tests help, but they don't replace a clinical diagnostic evaluation, helping stratify patients and differentiate the likelihood of Alzheimer's from other dementia syndromes with overlapping presentations. So typically speaking, if you're going to get one of these tests done, there is a what they're calling a three-cut off value. So there are below the threshold and you're pretty unlikely to have any disease. Above the threshold, you are pretty likely to have the disease. And in the middle, this is where we will use imaging to help adjudicate your level of risk. Okay, so this is this two-cut-off approach, the three-zone strategy is what I just described. Results above the upper threshold, high probability of Alzheimer's dementia pathology. Results below the lower threshold indicate low probability. High negative predictive value is what NPV stands for, 95%, meaning if your test is negative, there's a 95% chance you do not have the disease. Results in the intermediate zone require confirmatory testing with either amyloid PET, that's that brain imaging test we talked about, or cerebrospinal fluid biomarkers, meaning a lumbar puncture tap for more specific biomarkers. And using this approach, we can appropriately classify 80 to 85% of patients, which is pretty good. It's not amazing, but it's pretty good. And this is why, again, if you are not having symptoms, we have to be very cautious in how we do testing. I know that there are a lot of ApoE4 carriers who are interested in at least getting baseline values for PTAW7. And, you know, if you're doing that in conjunction with a like dementia specialist or somebody who's really working with you closely on your dementia prevention strategy, I think that's a reasonable idea. But just be clear, that's not necessarily part of the standard recommended clinical guidelines at this time. So higher beware, proceed with caution. Until next time, guys, take really good care.