New review of ketone neurochemistry and AD

[Julie G]

Amy, I find myself agreeing with just about every point you've made.

One thing to keep in mind; the line between preventing and treating Alzheimer's begins to blur in middle age for everyone, but especially for folks who are very susceptible- like us. The Alzheimer's disease process takes decades to develop. Many members want to make a sharp distinction between prevention and treatment; but experts in the field agree the line is actually pretty fuzzy. Until very recently, it was thought that once symptoms begin to manifest; Alzheimer's was a progressive, neurodegenerative death sentence. We have hints from newer research that we MAY be able to intervene.

IMO, we need to begin thinking of Alzheimer's as a continuum or a trajectory. IF we are lucky enough (as we are) to know our genetic susceptibility and we begin practicing prevention early; we MAY able to avoid or at least delay disease onset. Even if symptoms begin to show, we have suggestions that we MAY be able to reverse them. The recent FINGER trial from Finland and even Dr. Bredesen's recent paper Reversal of Cognitive Decline: A Novel Therapeutic Program http://www.impactaging.com/papers/v6/n9 ... 00690.html are two examples.

I agree that the relationship between cholesterol and heart disease is nowhere near as straight forward as Ancel Keys would have us believe; but the relationship between LDL-P and CAD does give us pause. Our members have good reason to proceed cautiously when trying to use ketosis as a therapy given our exaggerated response to dietary fat. We've worked hard as a community to try to glean benefit, while minimizing risk. (Strategies outlined above.)

I'm sorry you're feeling discouraged. From what I've observed many older people don't want to make dramatic changes to their diet or lifestyle. We have a few amazing members here who are shining exceptions. Many of us are struggling with our elderly parents on this front. These are the folks who tend to use ketone therapy/MCT once symptoms rear, without "patching the holes in the boat." It helps...a little, but won't be sustainable for obvious reasons.

On the other hand, WE are your target audience. We are motivated to make changes. I appreciate you taking the time to understand our more complex needs. Please feel free to share any time. (((Amy)))

[SarahAnne]

I am literally crying tears of appreciation for Juliegee and Amy right now. I'm 50 and feeling symptoms right in the here and now. This is not an abstract future for me and for many of us. As Amy suggested (and I hope I'm not overstating your views), I'm angry at all of these associations seeking to raise money and throw it into a political process that is virtually ignoring the kinds of interventions we're discussing.

I have read Dr. Newport's updated work about directly administering ketone esters as the coconut oil/MCT therapy showed diminishing returns with her husband. I have purchase both KetoForce and the newer, better-tasting, KetoCaNa (which appears to be out of stock now due to demand). The dosage is 11.7 grams of BHB per serving, and it may be taken up to 3x per day. It tastes very salty of course because it's made up of salts. It contains no fat of any kind.

So here's my question - If one feels their brain is in fact being starved, are you a fan of going full dose with these products 3x per day (in addition to a lower carb lifestyle), or would you take a lower dose approach? Is there anything risky about these types of salts... are they the same as regular sodium that might present risks if elevated. My blood pressure has always been very low, maybe too low (90/58 just yesterday...maybe I'll start a new thread about blood pressure). Anyway, I'd greatly appreciate discussion about ketone esters, their safety vis a vis sodium levels, edema etc, and how much to take.

Thank you, so much!!!

[Julie G]

SarahAnne, you are not alone here. I can’t help but notice that most of us struggling with cognitive decline in middle age are women… which is of little surprise. Cerebral hypometabolism occurs in E4 carriers even as young as our 20s-30s. It progressively worsens as we age. Any degree of insulin resistance exacerbates it further. When women begin to reach menopause, our estrogen production can drop precipitously. Guess what estrogen does? It's involved in transporting glucose to the brain. That quadruple whammy of E4, aging, IR, and menopause can set some of us over the edge… permanently. Many here have a handful of other predisposing factors that can even intensify this domino effect.

Many members experience improved cognition since adding ketone therapy. Trying to figure out the safest way to implement it, however, has been our dilemma. I hope Amy chimes in, but I will caution you that you are in unchartered territory here. Finding a physician to guide you in using ketone esters would be ideal, but close to impossible.

First, in the words of Dr. Stavia: think BIG picture. How is your overall health? Is your BMI in range? Do you have any belly fat? How’s your BP? What is your fasting blood glucose, insulin and A1c? Do you track post-prandial glucose? What do your standard lipids look like? Have you checked advanced lipids? If you’re showing ANY signs of insulin resistance, you MUST work on all of that concurrently with ketone therapy. Amy calls this “patching the holes in the boat.” In other words, supplementing with an alternative fuel is great, but you must give it the BEST chance to have a positive, sustainable effect by healing yourself of any insulin resistance and working towards optimal health.

If you’re dealing with menopause, consider HRT if you aren’t already using it. I had a terrific conversation recently with Dr. Roberta Brinton, a leader in HRT/Alzheimer’s. She is the one who makes the observation that some women do not make it through menopause cognitively intact. For many, that is the final insult that sends them over the edge. She has found that there is a window of opportunity, around a year I think, in which women who’ve experience cognitive decline with menopause that didn’t spontaneously resolve; can still reverse that process with HRT. Use our search engine, we have several LONG threads on HRT & even Dr. Brinton.

Dr. Bredesen has a comprehensive program outlined in his paper linked above that can help you attain optimal health and address other biomarkers (like Vitamin D, CRP, homocysteine, etc.) related to Alzheimer's. When speaking, he often refers to “patching the 36 holes in the roof” kind of similar to Amy’s analogy. No ONE therapy will sustainably reverse cognition. We hope that by addressing everything keeping you from optimal health, you’ll have the best chance moving forward. I’m so happy that you’ll be at The Buck to meet him and learn more.

Re. ketone esters, have you trailed them yet? Have you been using ketosis via diet, MCT, or other means previously? If not, I would move very slowly here and base EVERYTHING upon your response. Many here have been shocked by how badly we reacted to MCT- even in small doses. I stupidly took a TBS on my first trial and felt awful, like I swallowed rocket fuel. I do GREAT with a little ketosis, not so much with a lot. I would strongly recommend using a glucose/ketone meter to measure your response. Shoot for low levels of ketones, <1.0mmol/L at first just to measure your response. You might be surprised that you need a lot less than you thought. Going full dose 3X a day scares me a lot I would strongly suggest starting with a tiny dose and very slowly titrating up based upon your response.

Apologies for the lengthy response. YOU are most certainly not alone in trying to sort this out. Keep asking questions, my friends. And, PLEASE share your experience with the ketone esters. You're among the first to experiment with them. (((SarahAnne)))

[Tincup]

My blood pressure has always been very low, maybe too low (90/58 just yesterday...maybe I'll start a new thread about blood pressure).

For some reason, something about your post struck me that low blood volume might be an issue for you. Here is more info: http://askwaltstollmd.com/archives/mvp/160163.html

[TuitNutrition]

My knowledge of the effects of ketone salts & esters is virtually zero, so I don't feel qualified to comment on that at all. I would just echo Julie's advice to go slowly. I agree that the degree of ketonemia that might be beneficial for preventing cognitive decline might be less than we think. In the absence of herculean measures, it's pretty difficult to have super elevated ketones for any appreciable amount of time. (Like 4-8mM.) But I don't know that that's necessary. If the "normal" level of ketones in someone eating an average mixed diet is closer to 0.2-ish, then even getting to the neighborhood of 1.0-2.0 is ten times as much. I can't imagine that wouldn't have at least some noticeable effect. It's just guesswork at this point, but don't let that intimidate you. Go slowly and see how you do.

I wish there were more trials looking at ketone supplements in conjunction with reduced CHO diets. When some results have shown that E4s don't respond as well to ketone salts/esters, those studies usually employ the ketones with no other changes to diet and lifestyle. I have a hunch that even if blood ketone levels weren't sky-high, the efficacy of ketone supplements combined with a lowER carb diet, exercise, and other interventions might be far more impressive. I haven't written much about the topic of metabolic/mitochondrial flexibility, but someone who's been on a relatively lowER carb diet for a while -- especially when combined with exercise, good sleep, and possibly some intermittent fasting -- probably has more of the "metabolic machinery" in place to USE those ketones. (I am not an expert on this, but what good do ketones do if we're "wasting" them in the breath and urine? We want our cells to use them. Someone who's 70 years old, sedentary, and eats upward of 250g of CHO a day is probably NOT 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. (Enzymes, etc.) 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. (Maybe Bredesen will do this in the future -- add ketones to the existing protocol.) The caveat I would give is that this 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 more 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 trial go for 6 weeks and it be determined that this "doesn't work," when it might have been golden at 4 months...

See J. Stanton's presentation on metabolic flexibility: http://www.gnolls.org/3637/what-is-meta ... ng-slides/ (His focus is more on weight, metabolic syndrome, and overall health, but he's got some really good insights that I think are applicable to overall fueling of the body and brain.)

I've been careful to make the distinction between prevention versus slowing/reversal of symptoms because, in different "audiences," people have some pretty militant reactions on both sides of the argument. Some will argue for VLC diets for everyone, across the board, regardless of family history, athletic pursuits, body comp goals, or even anything at all to do with Alzheimer's. (Nora Gedgaudas seems to be in this camp.) And then, we have long-lived and healthy people who consume fruit, legumes, and other starches. It's a very tough road to walk. I've had some experience with clients who fall into the "orthorexia" category, and I like to talk them down from the ledge, so to speak, and encourage them not to focus so much on "not dying" that they forget to actually live. So there's a quality of life aspect to all this, too. From what I've gathered in my limited time on this forum, though, it's clear that most of you are far more motivated and disciplined than most average folks, and with the E4, you do have reason to be more careful and more concerned than ... pardon my saying, but someone with no known risk factors for much of anything, but who's terrified that half a sweet potato now and then might take them from a dress size 2 to a size 4. :-/

To Stavia: thanks for the hugs! Kind of embarrassed to admit how badly I need them.

P.S. Sorry that all my posts are so long! Let's just say that some days, I do freelance work from home, and I am starved for human communication, hehheh!

[Julie G]

(Maybe Bredesen will do this in the future -- add ketones to the existing protocol.)

FWIW, he is now From his paper:

-Optimize diet: minimize simple CHO, minimize inflammation. Patients given choice of several low glycemic, low inflammatory, low grain diets with the goal of minimizing inflammation, minimizing insulin resistance.

-Enhance autophagy, ketogenesis. Fast 12 hr each night, including 3 hr prior to bedtime with the goal of reducing insulin levels, reducing Aβ.

-MCT effects; coconut oil or Axona

[TuitNutrition]

Went for a long walk after my last post and did lots of thinking about this. I'm pretty sure I was clear enough before, but since I love thinking out loud, I wanted to share this and see what you think:

When we talk about metabolic & mitochondrial flexibility and efficiency, that includes how well someone is using ketones. (Or any other fuel, for that matter). So, really, even measuring blood levels of B-OHB really only gives us a sort of surrogate indicator. The levels of B-OHB in someone's blood tells us nothing about how effectively someone's cells are actually using those ketones. (Kind of like how the amount of cholesterol in any given lipoprotein particle says nothing about the degree of atherosclerotic plaque in someone's coronary arteries.)

Let's say someone has blood ketones of 4.0mM. That would be considered very good! But maybe they're not experiencing the improvements to cognitive function we would expect from levels that high. And let's say someone else measures ketones at 1.2mM. That's quite a bit lower, but maybe their mind is firing on all cylinders, and they feel great. So it's not necessarily what the numbers say, but rather, how someone is actually feeling and thinking. It doesn't matter how high ketone levels are if the cells can't use them effectively. (Think about nutritional supplements: you could have a 1200mg calcium pill of a form of calcium that's not very well absorbed, or a 400mg pill of a form that's more bio-available. You might get more benefit from the smaller dose because the body is able to use it. People who dislike using vitamin & mineral supplements say you'll just end up with expensive urine. So maybe people could end up with expensive blood, too. [Lots of ketones, but not using 'em.] I dunno...in most studies, higher ketone levels do generally correlate with improved cognition, but that seems to be why exogenous ketones have to be administered every few hours, because the effects are transient, especially if the body isn't producing elevated levels of its own.)

I think Julie is spot-on when she says how important it is to gauge things by how someone feels. (And if we're talking about someone already in the throes of MCI or AD, then potentially by whether caretakers and people close to that person observe a noticeable difference -- hopefully for the better.) We can use numbers as an indicator of how things are trending, and that's useful. I do think non-subjective measurements have a place in all this. But I also think we tend to downplay our own intuition and the signs our bodies give us. My body and mind (and spirit, if I can say so, without getting too "woo-woo") tell me when I'm feeling fantastic; if I bother to use a urine test strip, it's only to confirm what I already knew.

We hear talk of "keto-adaptation" mostly as it applies to athletic performance, but it also applies to everyday folks not doing Ironman triathlons. And if it takes a few weeks for young, healthy, physically active people to fuel themselves adequately with ketones, what does that say about middle-aged and elderly people, who might have the added challenges of metabolic syndrome, sarcopenia, decreased liver function, etc? I still think a lower-carb diet combined with other lifestyle factors and possibly exogenous ketones will give people the best shot at preserving and/or improving cognitive function, but it might take a while before easily observable effects are seen.

[Stavia]

Amy, your train of thought is intruiging. Thank you for taking the time to type it all out. I hope very much that it is true for us. Its a very hopeful paradigm.
And yes, our little group IMO is very special. I talk myself blue every day as a mainstream doctor (not in the USA) to sick people with sick lifestyles. Maybe I can get one person to make significant changes a couple times a year. Everyone wants a magic pill. Some days I feel like I'm peddling snakeoil, because in the presence of a sick lifestyle, that's about the difference a single intervention will make. I share your disheartened feeling at times (((Amy))).
So I hope very very much that our group is building a strong healthy foundation with all the bricks firmly cemented. So each intervention will be additive.

[SarahAnne]

I want to thank Amy, GeorgeN and Juliegee for the great input. I have been working on realigning my lifestyle for months, ever since Dr. Bredesen's report was published last October. It has been a huge undertaking, from sleep studies, to heavy metals, to when I eat and sleep, hormone alignment, and on and on and on. So much time and expense, but it's interesting and worth it. I can only imagine trying to get an unmotivated patient to make such changes or any changes like these! This thread has given me some great information to "unpack" and figure out how to apply. Many thanks again:)

[Julie G]

Good for you SarahAnne! It sounds like you're on a really healthy path. I know it feels like a lot when you make the changes all at once, but incorporating them gradually makes this new lifestyle more doable. Kudos on the improvements

Really interesting presentation by J. Stanton. Thanks for sharing Amy. It helped this non-scientist wrap my head around a few important metabolic concepts.

I would definitely consider myself to be in recovery from severe metabolic inflexibility. I was stunned to learn that we first lose the ability to oxidize fat, then glucose. That explains a few bad episodes I experienced where I actually lost consciousness from severe hypoglycemia. Ketones couldn't rescue me if my body couldn't use them- I get it now. Understanding that the loss of fat metabolism is driven by mitochondrial dysfunction seems to indicate that this may be a BIG issue for E4 carriers. And, YES, all of this certainly plays into our early cerebral hypometabolism.

I love that exercise is touted as being key to revving up the mitochondria. No wonder that is the most "proven" of all strategies to prevent E4 driven pathologies.