June 26, 2015

Alzheimer’s, Ketones, and Kidding Ourselves (Pt.3/3)




I concluded the previous post by introducing the idea that, when it comes to a body and brain being fueled by ketones, the absolute concentration of ketone bodies in the blood might be less important than the body’s ability to use those ketones. I expressed concern that placing the sum total of our faith in high β-OHB levels might take our eyes off the marker we should probably be more interested in: how well an AD patient is functioning. Maybe some AD patients do require ketones at upwards of 4-5mM. But maybe some others would do just great at lower levels.

Heres my thinking on this...




Missing the cognitive function forest for the numerical trees


Let’s say someone has blood ketones of 4.0mM. That would be considered crazy good! But maybe that person isn’t experiencing the improvements in cognitive function we would expect from levels that high. And let’s say someone else measures ketones at 1.4mM. That’s quite a bit lower, but maybe their mind is sharp and they feel great. So it’s not necessarily what the numbers say, but rather, how someone is actually feeling, thinking, and processing information. It doesn't matter how high ketone levels are if the cells can’t use them effectively. (Think about nutritional supplements: you could take 1200mg of calcium in a form that’s not very well absorbed, or 400mg in a form that’s more bio-available. You might actually experience a greater benefit from the smaller dose, because the body is better able to use it. People who argue against using vitamin & mineral supplements say youll just end up with "expensive urine." So maybe it’s possible for people to end up with expensive blood, too. [Meaning, lots of ketones, but not using them to the best effect.]) 

The truth is, in most studies that employ exogenous ketones, higher ketone levels do tend to correlate with improved cognition. I don’t deny this. BUT: exogenous ketones must be administered every few hours, because the effects are transient. Like I said last time, when they wear off, they’re gone. Fin. Kaput! (And according to researchers, the half-life of elevated β-OHB in the blood induced by exogenous ketones is only about 1-1.5 hours. Not all that long.) 

But how might that compare to someone on a low-carb diet, doing a little fasting, lots of fat-fueled low-level physical activity, and maybe taking a couple spoonfuls of coconut oil here and there? This person would have elevated ketones all the time. (Maybe not 3-5mM, but certainly more than the 0.1-0.2mM typical of a balanced diet [i.e., high-carb].)

I keep going back to the LC versus KD thing, because I think it’s an important distinction to make, particularly when we have researchers making claims that boil down to, “It’s just too hard for people to change their diet, so that’s why we’re so excited about these ketone formulas.”

People might be more inclined to change their diets (or that of their loved ones) if they thought they could see some pretty good improvement by doing, say, a regular ol’ Atkins diet, rather than a 4:1 or 3:1-style medical ketogenic plan, where they’re living on avocados, macadamia nuts, cream cheese, butter, creamed spinach, and asparagus drenched in hollandaise sauce, and are about to puke from all the fat. Yes, when you need to restrict protein and get upwards of 80% of your calories from fat, a KD is difficult to maintain. You do almost have to arrange your life around the diet. But a regular ol’ low carb approach? Easy-peasy! (BTW: for those of you who don’t know, the real, true Atkins diet includes plenty of vegetables and even fruit, depending on one’s carbohydrate sensitivity. It is not all bunless bacon cheeseburgers. Please stop believing the stereotypes about this absolutely lifesaving nutritional plan.)

And the beauty of a more general low-carb approach is that it is completely workable in everyday real life. Millions of people have been doing it for years. As a low-carber myself, I’ve never found myself in a social situation or at a restaurant where I couldn’t find anything appropriate to eat. Eating on the go has never been a problem, and it’s really not difficult to stick to when you can eat (depending, of course, on individual carb tolerance) upwards of 75-100g of carbs a day. You don’t have to live on heavy cream and bacon. (Though that would be tasty!) You can enjoy strawberries, whole-milk yogurt, dark chocolate, and semi-massive piles of greens and other low-starch vegetables. (Even small amounts of carrots, beets and winter squash!) It’s not difficult. It’s easy to buy groceries, easy to prepare meals, easy to eat on the run, and you don’t have to drive yourself crazy about the macronutrient ratios and stress about limiting protein. I think this is where the researchers are missing the boat. They’re confusing “low carb” with a no-sh*t, crazy-strict ketogenic diet.

So again, let me speculate: someone on a LC diet, with the fatty acid and ketone-using pathways ramped up and going 24/7—as opposed to someone following their same-old high-carb diet and insulin-resistance-inducing lifestyle, and just taking exogenous ketones every few hours—might (might) extract a bigger benefit from a lower level of ketones. (This being said, I certainly acknowledge that there are people who do need to follow a very strict ketogenic diet and get ketones up around 3-5mM in order to see benefits. I just think they might be in the minority. If nothing else, folks can start with a solid LC diet, see where that takes them, and refine the macronutrient ratio as necessary, over time.)

I wish there were more clinical trials looking at ketone supplements in conjunction with reduced CHO diets. There are currently very few, if any. They almost all employ only the ketone esters, but there are some more in the works, and we already have great indications that carbohydrate reduction combined with other lifestyle adjustments can have stunning impacts for AD and MCI.

Someone who is 70 years old, sedentary, and eats upward of 200g+ of CHO a day is probably not all that metabolically flexible. So we dose them with exogenous ketones, and maybe they get a small benefit. But would we see a much bigger (read: better/more effective) benefit in giving the same ketone dose to someone whose mitochondria are primed to be able to use that fuel properly? We tend to forget that we can't just shove certain compounds into our bodies and expect to automatically get the intended benefit. Certain physiological/biochemical mechanisms have to be in place in order to use them effectively. This is why I think the combination of outside ketones and a lower carb diet (and exercise, and anything else that improves insulin sensitivity and metabolic flexibility) would show much more promise than we’ve seen so far in studies where they administer ketones but require no other changes to diet or lifestyle.

The caveat I would give for a study looking at a LC diet for AD is that it would have to be a fairly long-term study, especially if the subjects are much older. The younger someone is, the more likely they can adapt quickly to a dietary change. For someone of advanced age, and advanced AD, it would probably take longer for them to bring the metabolic machinery up to speed. I would hate to have a clinical trial go for 6 weeks and it be determined that the approach is “ineffective,” when it might have been golden at 3 or 4 months.


Confounding factor: ApoE4



We need to talk about ApoE4.

Considering how long this post has already been, I won’t inundate you with the whys and wherefores of the ApoE4 genotype. Nutshell version: ApoE4 gene carriers (both hetero- and homozygous) have a markedly increased risk for developing AD. There are many reasons for this, but one of them seems to be related to lipid/lipoprotein processing. (E4s tend to have freaky high risks for cardiovascular disease, as well as Alzheimer's.)

The reason we need to talk about ApoE4 (which I’ll just call E4 from here on) is because, in studies where exogenous ketones have been used to improve cognitive function in AD patients, E4 people usually don’t show as profound an improvement as other genotypes, and sometimes they show no improvement at all. What gives?

This, my friends, is why I am so passionate about the importance of dietary and lifestyle changes. Study results showing that E4s dont respond as well to ketone salts/esters as E2s and E3s typically employ the ketones with no other interventions. I understand that the ketone variable does need to be studied in isolation, to make sure it really is the ketones and not some confounding factor that is having the effect, but once it’s established that ketones do help—and this has already been established (at least, in non-E4s)—then it seems the right thing to do for the E4s isn’t to throw our hands up and give up, but rather, to ask why the E4s don’t get the same benefit as the other genotypes. My hunch—which is backed up by a significant body of research—is that the E4 genotype does not program anyone to develop AD. What it does is make its carriers the most susceptible to the detrimental effects of the modern diet and lifestyle. (Kind of like how the BRCA1 genes don’t cause breast cancer, but they increase susceptibility.)

According to the people who eat, sleep, and breathe this stuff:

The APOE Ɛ4 allele may not be inherently damaging but only in combination with a high-carbohydrate diet, which is damaging in itself and is likely to be a major contributor to the high risk of CAD [coronary artery disease], and possibly AD, in modern populations with or without the APOE Ɛ4 allele.” (Lane & Farlow, 2005)

“It should be noted that E4 is not an inherently damaging allele; it is only deleterious in combination with a HC [high-carb] diet (which is deleterious on its own).” (Henderson, 2004)

“A modified ‘Paleolithic prescription’ may prevent AD. The Paleolithic prescription proposes a change in diet and activity to a level more similar to our Late Paleolithic ancestors. […] Therefore, reducing dietary intake of high-glycemic carbohydrates and increasing protein, fiber and fat would be preferred. Similar diets appear to reduce the risk of AD. Since HC [high carb] diets are proposed to be the primary cause of AD regardless of apoE genotype, such a diet would generally reduce the risk of AD. However, this diet is predicted to be particularly beneficial to carriers of apoE4.” (Ibid)

From the study that inspired this post: (“the patient” is referring to Mr. Newport)

“Given the report by Henderson et al. indicating that the APOE ε4-positive subjects in their study failed to show statistically significant improvement in their ADAS-Cog scores in response to MCTG treatment, it is noteworthy that the patient, although APOE ε4-positive, exhibited clear cognitive and behavioral improvement while consuming equivalent or larger quantities of ketogenic MCFAs. The findings of Henderson et al. (which may have lacked the statistical power to detect a change in APOE ε4-positive subjects) do not rule out the possibility that carriers of the ε4 allele could show cognitive improvement if studied for longer periods of time and/or given higher doses of MCTG.”

You know what else the findings of Henderson et al. don’t rule out? How about the potential efficacy of smaller doses of ketones (or higher) combined with a freaking low-carb diet?!  (And maybe a little fasting here and there, some long walks, and good sleep.)

Maybe the exogenous ketones didn’t feed the starving neurons of the E4s because these folks were still eating pasta/bread/cookies/whatever, still not sleeping enough, and still being too sedentary, and there are only so many roadblocks outside ketones can overcome. What might happen to cognition in E4s when we provide some exogenous ketones, but their bodies are champing at the bit to use them, because the metabolic machinery is in place for them to do so, thanks to a low carb diet and whatever additional lifestyle modifications they are capable of? 

Another reason I wanted to address the E4 issue is that LC diets often—not always, but often—include high amounts of saturated fat. And since the E4s have exaggerated lipoprotein responses, they might need to adjust things a bit. I am not an expert on the ins and outs of E4. (But these folks are. Also here.) All I know is, with consumption of high amounts of saturated fat, E4s tend to have very elevated LDL cholesterol – and I mean very elevated, in both cholesterol content and particle number. They might also show unfavorable changes with high consumption of other types of fat, but saturated seems to have the biggest impact. (We in the LC/Paleo worlds generally don’t freak out about cholesterol like the mainstream medical world does, but there’s a lot that’s yet undetermined, and until we know anything for certain, it’s not unreasonable for these folks to be concerned.)

That being said, there’s no reason an E4 can’t construct a LC diet based on mono- and polyunsaturated fat. And, when combined with other lifestyle interventions that might help maintain/restore insulin sensitivity, it’s possible that they wouldn’t even require carbohydrate restriction to an extreme degree. I could see a place for 25-30% carbs in someone who’s got everything else in check, particularly if those carbs are coming from non-starchy vegetables, lower-glycemic fruits, and yes, maybe even small amounts of starchier foods. So it’s possible to have a lowER carb diet without it being super-heavy on fat, which seems like a prudent way for E4s to approach this. Some people might be able to get the cognitive benefits of a low-carb diet without being uber-ketogenic at all times.

My personal opinion is, getting ketones higher is probably a good thing for ALL people whose brain cells’ utilization of glucose has become compromised—regardless of genotype. But in order to balance long-term cardiovascular health and preservation (or restoration) of cognitive function, perhaps the E4s might do best on a ketone supplement combined with a low-ISH carb diet, rather than an ultra-low carb diet.


Either way, my purpose in writing these posts is this: if we think exogenous ketones alone will be some kind of miraculous silver bullet for Alzheimer’s disease, I think we’re kidding ourselves.








Remember: Amy Berger, M.S., NTP, is not a physician and Tuit Nutrition, LLC, is not a medical practice. The information contained on this site is not intended to diagnose, treat, cure, or prevent any medical condition.

18 comments:

  1. Whoa. The information about the ApoE4 is fascinating to me! I'd never heard of it until reading this post. But, it makes me wonder if this runs in my family given my family medical history. Is there a way to test for this gene? Or would doctors basically scoff at someone for asking?

    The more and more that I learn about the wide benefits of eating low-carb or ketogenic (even if some of them are scientific speculation!), it makes me question why we still have such a huge dissonance within the medical community. Why is it that one of my in-laws, who is a registered dietician, specifically told me that low-carb was 'dangerous' and that I shouldn't be on it, even though I clearly exhibit a lot of signs of insulin resistance? It just blows my mind that the very people who we trust to take care of our medical needs are the exact people who may be harming us with the concept of the "heart-healthy, whole grain" diet.

    Great series! Thanks, Amy!
    -Nikki

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    1. Hey Nikki, yes, there are tests to find out your ApoE genotype. It's not the kind of thing a typical family MD would order, though -- if they even know anything about it. 23 and Me will tell you, and there are probably some other companies out there that allow you to do it privately. (You'd have to pay out of pocket.)

      As for the other issue -- bringing low-carb to the mainstream medical profession, it's still an uphill battle, but the times are definitely (if slowly) changing. There have been high=profile articles in some pretty well-respected medical journals that support ditching the limits on cholesterol, total and saturated fat, and bringing more attention to the negative effects of sugar and excess CHO consumption. It's going to be from the ground up, though, as is happening with the low-carb and Paleo movements. Thousands of people whose doctors were able to provide no help whatsoever, or maybe even made things *worse,* found out all on their own that maybe all they needed to do was go low-carb, or ditch the grains and cottonseed oil. And when doctors start to see that people are having extraordinary improvements in their health by doing the *opposite* of the conventional advice, we would hope that *eventually,* those docs get curious enough to start questioning the dogma.

      The conventionally-minded RDs are a hoot. I would say it's almost impossible to understand basic human biochemistry and physiology and *not* understand how a low-carb diet could be effective. (Not just for fat loss, but for all the other things it does, too.) And I *know* they get plenty of training in the science, so it seems like somewhere along the way, they forget all of it and tell people that a fat-free muffin with some margarine and/or strawberry jam, plus a glass of OJ, is a good way to start the day...

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  2. Thanks for the series! I'm particularly interested in the bit about APOE4 because myself and both of my parents are e4/e4 based on 23andme testing. Could you let me know what study makes you say this, if you have it handy:

    All I know is, with consumption of high amounts of saturated fat, E4s tend to have very elevated LDL cholesterol – and I mean very elevated, in both cholesterol content and particle number.

    ?
    Reading all of this makes me glad I got into ancestral health ~4 years ago. If I found out about all of this stuff when it goes mainstream in 15 years, I'd be pissed!

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    1. Hey Rob, I'll have to look for some specific studies, but if you poke around the ApoE4 forums (http://apoe4.info/), you'll see these people are *very* concerned about risk factors for both cardiovascular disease and Alzheimer's. (Links are included in this blog post, under the section about E4.) ApoE4 is pretty well known for conferring increased risk for Alz. I know of less info right off the top of my head regarding cardiovascular issues, but that also seems related to lipid & lipoprotein processing in that genotype. A PubMed search would probably turn up more than you can even imagine. Maybe start here:

      http://www.ncbi.nlm.nih.gov/pubmed/10738542
      http://www.jlr.org/content/46/5/949.long

      If you can't access the full text and would like to read the articles, let me know.

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  3. Hello Amy, good stuff as always. After reading a hundred or so E4 studies (which confers an honorary PhD from the online school of Cleverclogs Inc.), I would argue the association with CVD is nowhere close to the AD association. There are probably just as many that don't find a link, or if they do, it's a weak one. Not to mention the plethora of papers that purport to say E4s have high risk, simply because they have higher LDL numbers - that is awesome science.

    There are also many that have lipids listed and compared with E3s and E2s and it's quite clear that none of them can be sanely transferred to an E4 who is truly limited carbohydrates. Triglycerides are a dead give away. Of course the "high fat" diets that some play with are anything but (40%+ cho)..so much wasted effort...shit methods produce shit.

    If I had a few hours I'd trawl through my stack of papers and dig some out, but unfortunately it's Saturday arvo and life is short. Good excuse or what?

    OK, here's one - http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3310005/

    CONCLUSION: Under standard medical treatment of diabetes, including the control of LDL cholesterol levels, the apoE4 isoform was not associated with coronary heart disease among T2DM patients.

    Of course I'm cherry picking, but that should be pretty obvious. I can't remember exactly what's in it, so the conclusion could be misleading. That one is actually quite interesting due to the diabetic aspect. HbA1c is significant...holy crap. Ha.

    Going off the AD topic, unfortunately, but all the dancing around E4s association with CVD appears to always come back to lipid levels, which are a bit tiresome. For me, at least, but I freely admit I could be full of shite. Time will tell.

    Keep up the excellent work, Amy.

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    1. I'm with ya. There's a lot we don't know, but it does seem like some (most?) of the concern around E4 and cardiovascular risk is based on lipoprotein markers -- particle numbers, particle size, cholesterol content, and not necessarily "hard endpoints." But I understand the concern people have in whatever useful information those surrogate endpoints might provide as *indicators* of risk for an actual CV event -- heart attack, stroke, etc. But I agree with you -- I think we still don't know the full story about what certain markers mean in the context of most else looking good, like trigs, A1c, HDL, maybe even also fasting insulin, blood pressure, etc. Seems like most of the data we have was/is collected from people consuming non-low-carb diets, and we can't say how, exactly, some of those markers might mean different things for people who eat very differently. I'm not educated enough in the ins & outs of the specifics with E4 to say more, but I couldn't write posts like these without at least mentioning the topic.

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  4. Referring back to the first section of your post - the 'Impact Aging' study you link, while small, is particularly revealing. It isn't often reported but it is common enough that with late onset diabetes there is significant mental decline, loss of short term memory function etc. I can verify this personally --- ten years ago I really thought I was losing my mind and the future was bleak. Given that occult diabetes is very common, more common than most doctors realize, it is not even slightly surprising that correcting blood sugar control with LC types of diet, exercise, good sleep and nutrients, drugs if necessary, can bring great improvements.


    C.

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    1. Thanks. Yeah. that study is fantastic. I'd like to see it expanded to a much larger number of subjects, and of course, I'd like to have more data about the exact diet(s) some of them were following. Dr. Bredesen (author of the study) is still hard at work, so hopefully we'll have more good info in the future. An article criticizing Dr. Perlmutter's work was released recently, but if you put any stock in what he says, here's a line from his book, Brain Maker: "Make no mistake: blood sugar regulation is priority #1 when it comes to preserving brain function and resisting Alzheimer's disease."

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  5. Wonderful post Amy, you really should be a health writer for a major mag so as to reach so many people who are just told the same old crappy advice. I like the way you simplify how a LC an be easily incorporated without too much fuss. This would make it more acceptable to the public and hopefully the medical establishment. Most MD's still see it as just eating huge amounts of fatty meats. I get rolled eyes if I tell them I'm LC and lectured that I shouldn't cut out food groups and eat too much fat/meat, so now I just say I'm on a modified Mediterranean Diet which seems to shut them up. The other problem is getting people off their beloved bread/cakes/muffins/french fries/Yoghurtland..this is a major obstacle for most...they can't do it. Doesn't help that we are bombarded with these foods everywhere we go. People are souvenir eaters, can't visit anywhere without having something to eat. Anyway, am so enjoying your posts, interesting and funny, thanks so much.

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    1. "Souvenir eaters" -- what a great phrase! And you're so right -- in the U.S., everywhere you go, there's food. And I mean *everywhere* -- even an electronics store, or a shoe store! Thanks so much for the compliments. :) I really love writing the blog, so it's great to know people enjoy reading it.

      I'm with you on low-carb -- I try to make it sound non-threatening, and do-able in the real world, because it is! And depending on one's state of health and individual metabolism or disease state, there really *is* a little wiggle room for some people with regard to sweets. Certainly not in the amounts and frequency we typically eat them in the U.S., but if someone can limit things to just *once in a while,* that might make them better able to stick to LC for the long-term.

      Modified Mediterranean is a good phrase, too. I can see how no one could really argue against that. I'm perfectly happy telling people I'm low-carb, but when people tell me they're going to their doctors, I usually suggest they not use those words, but rather, just say they're cutting out sugar and grains, eating lots of good vegetables, healthy fats, and quality protein. 'Cuz really, that's what it is. Some people will load up on fat, but not all of us.

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  6. What a great series of articles Amy ... thank you.

    " the beauty of a more general low-carb approach is that it is completely workable in everyday real life. " it sure is I just wish more would do it ... but the word is spreading.

    Thank you for taking time to do these articles. Sorry my comments have all come through at once but as I said I've just caught up with reading them.

    All the best Jan

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    1. No worries! Never a need to apologize for leaving positive comments. :) (Heck, it's nice just to know someone out there is reading these things!)

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  7. Amy, Thank you, thank you! I've recently discovered your publications. My husband, age 67, has recently been diagnosed with dementia (not sure how this differs from Alzheimers). Our doctor recommended we switch to a ketogenic diet, and we have been strictly following the guidelines for about 4 weeks. Among other books, I've read Dr. Newport's, Ellen Davis's Diabetes, and your Alzheimer's. You give me a lot of hope and I thank you. My question as a result of this 3 part post: are "exogenous ketones" available for me to purchase and add to my husband's regimen? He has recently begun Namenda and Aricept, which I was hoping to avoid. Conventional medicine pushes it, and I'm not confident enough to refuse them.
    Again, thank you so much for giving us hope in an otherwise hopeless diagnosis.
    Jane

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    1. One more thing...
      I did a podcast interview with Jimmy Moore recently, about my Alzheimer's book. We probably didn't cover anything you don't already know, but in case you're interested, you can check it out here: http://www.thelivinlowcarbshow.com/shownotes/12494/967-amy-berger-examines-the-ketogenic-antidote-to-alzheimers-disease/

      And I wrote a blog post where I addressed some of the things I didn't get to talk about in the podcast, since it was only about a 30-minute recording: http://www.tuitnutrition.com/2015/06/podcast-interview-alzheimers.html

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  8. Hi Jane, so glad you've found this information. And how great to hear that the doctor is on board with the keto approach. That's fantastic! There are exogenous ketones available, but they're a little pricey. You can check out one company that makes them here: https://pruvit.wistia.com/medias/akyqf0ja10

    If you're on Twitter, write to brandonbKC77. He knows a lot about them.

    Please stay in touch and let me know how your husband is doing! We need more people to try the low carb approach so we can start amassing some testimonials. And feel free to tell that doctor about my book. Maybe more of his patients could benefit from it. :-)

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  9. Hi Amy,
    I agree with your hypothesis that exogenous ketones would be best employed in conjunction with a VLC diet, and even IF, but that’s because I came to that conclusion for myself, backwards.
    I have been eating VLC (pretty much) since 2002, but since I’m not perfect, the idea of supplementing it with exogenous ketones occurred to me after I attended the Metabolic Therapeutics Conference in Tampa in January. I was especially impressed with Mary Newport’s presentation. I also like the idea of using them as a prophylactic intervention, although my wife would argue that it is a combination prophylactic/therapeutic intervention in my case.
    A few weeks before the January meeting, after watching an Andreas Eenfeldt video, I also began Intermittent Fasting (18:6), 7 days a week. Since I am already ketoadapted, I was never hungry at breakfast and now often skip lunch too. I am doing this both to lose weight and to force my blood sugars below 100mg/dl. Over the years, that’s gotten harder to do that with diet alone (plus a little metformin).
    The exogenous ketones I am taking are in gel form. They are 6g of MCT, 6:1 ketogenic ratio and are very palatable and convenient to use (in a small foil package). But, as I learned in this series, ßOHB has a half-life on only 1-1½ hours, so the question I have is when to take them. I have been taking them as the breakfast table (with pills and water), and my wife, but at “breakfast” I am already in ketosis after an overnight fast. The insight I have gained from this reading is that perhaps I should be taking them with my supper (basically my only meal of the day). It is also the only time in the day that my serum glucose rises, also for just 1-1½ hours (theoretically).
    That raises the question, “Will the brain use these exogenous ketones if it has a choice?” Or will it prefer the glucose from carbs and protein in the evening meal? Remember, I want these FFAs to go to my brain, not my waistline. I wonder if while trolling the academic literature, you have gleaned any information or otherwise have thoughts or insights in this connection.
    Dan Brown

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    1. That level of nuance is really beyond my knowledge. Anything I might say would purely be speculation... Sorry!

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    2. I think you will find the answer to your question in one of these videos. I just watched them both but can't remember which one said it! Basically, what they said, is that if you add exogenous ketones, the brain will use them in preference to glucose and correspondingly will reduce its uptake of glucose. It is well worth watching both these interviews as they are both fascinating. https://www.youtube.com/watch?v=BhywHFWFABo https://www.youtube.com/watch?v=bM7N40mC3Xc

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