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New review of ketone neurochemistry and AD

Insights and discussion from the cutting edge with reference to journal articles and other research papers.
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MarcR
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New review of ketone neurochemistry and AD

Postby MarcR » Sun May 03, 2015 12:34 am

I found this new review to be worth my time for its integration of insights from many studies into a plausible neurochemical exposition of Alzheimer's pathology. With 160 references, the review is thorough and does consider ApoE ε4; that it ultimately offers no explanation for the ineffectiveness of ketone supplements in ε4 carriers indicates to me that no relevant research has been published yet. Thanks to Amy Berger (member TuitNutrition) for mentioning the paper in this recent blog.

The paper offers one actionable insight. In individuals with cerebral glucose hypometabolism, moderate ketone concentrations boost cerebral energy and inhibit Aβ-triggered neuronal death, but high ketone concentrations like those used to control epilepsy may suppress a key brain function (glutamate synthesis).

The entire Brain hypometabolism precedes clinical signs of Alzheimer's disease section is good, but I want to highlight this especially:
As mitochondrial DNA is maternally inherited in humans, it is interesting that brain glucose metabolism is lower in elderly with a maternal family history of Alzheimer's disease than in those with a paternal family history and in controls with a negative family history of Alzheimer's disease (Mosconi et al. 2007). Furthermore, in cognitively normal persons between 32 and 72 years of age with a family history of Alzheimer's disease, brain glucose metabolism is lowest in those where both parents had suffered from the disease, intermediate in those with a maternal history of the disorder and highest in those with a paternal family history (Mosconi et al. 2014).

Much of the paper is devoted to a complex, fascinating hypothesis that AD originates in the brain stem with tau damage to a small structure that provides the brain's adrenergic stimulation. Impaired stimulation accounts for the early cerebral glucose hypometabolism in people who later develop AD. Tau-damaged brain stem nerve cells release amyloid beta into the rest of the brain, and the anti-inflammatory and repair responses are inadequate because of the glucose hypometabolism. The paper does not hypothesize a cause for the tau-related brain stem damage.
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Re: New review of ketone neurochemistry and AD

Postby Stavia » Sun May 03, 2015 3:15 am

Good find!
I was wondering months ago about the mitochondrial DNA angle. And the dose dependent effect hypothesis is intruiging. Thanks so much for posting.

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Re: New review of ketone neurochemistry and AD

Postby Juliegee » Sun May 03, 2015 11:38 am

Thanks for sharing, Merouleau. I’d not seen this paper before.

The notion that cerebral hypometabolism precedes clinical signs of Alzheimer’s is irrefutable. It’s incredibly disappointing to see the relative lack of research on modulating this upstream of other effects. This paper cites Dr. Henderson’s work where we see E4 carriers demonstrating no response (even a slight worsening) with keto therapy. Dr. Henderson has revealed that he is currently working with an E4 positive group trying to get an improved response. I think results of that will be available this year:

The positive response was restricted to patients who tested negative for APOE4, whereas APOE4-positive patients showed no effect or even a minor deterioration (in spite of the more pronounced hypometabolism in APOE4 carriers described in section 'Brain hypometabolism precedes clinical signs of Alzheimer's disease’).


My guess is that E4 carriers don’t show improvement because they were already in moderate stages of the disease and had too much underlying pathology at the time of this intervention. The graphic below reminds us of the myriad ways E4 carriers are affected, as opposed to other apoE genotypes. It makes sense that any single modality therapy is less likely to work on our population, especially applied later in the disease process. It doesn’t necessarily mean that addressing our demonstrated cerebral hypometabolism is NOT a good idea.

APOE_gain_loss.jpg.png


From everything I’ve learned, a multifactorial strategy (like Dr. Bredesen’s,) applied as early as possible may give us the best chance of avoiding or delaying onset of neurodegneration. I'm anxious to see the E4 data from the recent FINGER trial in Finland that demonstrated via RCT that a multifactorial strategy CAN work.

In epilepsy, it appears advantageous to administer the highest possible fraction of the patients’ calorie need in the form of ketone bodies, which may reduce glucose metabolism sufficiently to impair glutamate production in neurons. Much lower doses of ketone bodies can have therapeutic effect in Alzheimer's disease by different mechanisms.


This is interesting and addresses some of Richard’s & Dr. Ballantyne’s concerns. A VERY strict (low carb/high fat) application of a ketogenic diet is necessary with epilepsy, but may not be with Alzheimer’s. Perhaps that offers us the opportunity to deal with reduced negative side effects?

Lastly, I read Amy Berger’s blog post. I LOVE that she is taking the reduced cerebral hypometabolism message to the masses, but my guess is that her “FIX” is over-simplified and not ready for prime time- certainly NOT for our population. With our perturbed fatty acid metabolism and multitude of other challenges, her cure (unless dramatically modified; as many are doing here) may do more harm than good.
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Re: New review of ketone neurochemistry and AD

Postby MarcR » Sun May 03, 2015 3:50 pm

Juliegee wrote:Lastly, I read Amy Berger’s blog post. I LOVE that she is taking the reduced cerebral hypometabolism message to the masses, but my guess is that her “FIX” is over-simplified and not ready for prime time- certainly NOT for our population. With our perturbed fatty acid metabolism and multitude of other challenges, her cure (unless dramatically modified; as many are doing here) may do more harm than good.

I enjoy Amy's blog and have learned a lot from her - in addition to her Type 3 Diabetes: Metabolic Causes of Alzheimer’s Disease review, which we have discussed here from time to time, I found her series on cancer to be a real eye-opener.

As a nutritionist, she seeks to help people who are eating the SAD, IR, obese, sedentary, and beset by symptoms of chronic disease. She looks for clients like her mom, who died last year. She tends to express her views with a high level of certainty, which I think is helpful to people who are struggling with the basics. I have not read her book, but from her other work I suspect that her prescription for AD prioritizes resolving IR over optimizing lipids. If so, I think that's a good choice regardless of ApoE status for the population she's trying to reach.

Personally, I appreciate the clarity of Amy's certitude when I'm learning something new to me, but I also read her work as a mixture of scientific review and advocacy. I don't expect her to be even-handed or nuanced as she is trying to help people who need crystal clear guidance.
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Re: New review of ketone neurochemistry and AD

Postby Juliegee » Sun May 03, 2015 4:13 pm

Merouleau, I'm also a fan of her general message; BUT we are a special group and clearly need a more nuanced approach ;)

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Re: New review of ketone neurochemistry and AD

Postby marthaNH » Sun May 03, 2015 8:00 pm

Just want to say I got a lot out of this discussion and appreciate your sharing the new (to me) study and just kicking it around generally. I have been a little flabbergasted by the other current thread here that recently seemed to argue that even mild ketosis brought on by exercise and refraining from eating was something that ought to be feared until proven safe, or something. I am not going to gin up any anxiety about skipping a few meals or having low-carb days, especially seeing the clear benefits I've enjoyed across the board from a lower-carbohydrate diet.

So thanks for giving me something useful to read instead. I'm sooner or later going to report back on the higher-carb, variation heavy experiment but have been too wrapped up in work, life, family to focus on it.

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Postby Stavia » Mon May 04, 2015 6:11 am

Excellent discussion team. I was thinking that the method that many of us use for our dietary optimisation (short feeding window, low starchy carb yet abundant leafy carb/ moderate protein hence higher fat, excercise) would result in mild ketosis in many of us who prolly don't even know they are in mild ketosis because they haven't tested. I can't see how this could be harmful and it's blinkered to lump this with a very high saturated fat very low carb diet and damn them both. IMO there is a huge difference. The latter is likely not to be the best for us and one cannot IMO extrapolate it to our current common approach.

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Re: New review of ketone neurochemistry and AD

Postby MichaelR » Mon May 04, 2015 6:16 pm

After the confusion and hurt I've apparently caused in the other thread, :oops: and seeing that a response to both that mess and the comments and questions on the substantive issues underlying the post itself, a response is taking me a while. However, there are even more basic misunderstandings that are only becoming clear to me in this thread. So before things go to far, let me first apologize: in a generalized way to those I've upset or annoyed, but also personally and directly here to Juliegee. Julie, I wasn't clear on how much you still find David Perlmutter's views informative, and certainly had no clue that he was actually part of your clinical team. I meant no offense to anyone here (though I admit I'd not have been upset if I had learned that DP was lurking and annoyed ...), and certainly didn't mean any slight toward you: you are too positive, too supportive of this community, and make too many valuable contributions from which I and (clearly) many on these Boards value.

I have a generally blunt and aggressive style of debating (and have actually worked to be more careful about this over the years ... Julie can consult a mutual friend for my alibi ;) ), and am also genuinely offended by what I must say I see as intellectual dishonestly in much of DP's argumentation, and have felt compelled to refute it when it is invoked. That said, I did not and do not participate in this Forum with any specific intent to attack him: it's rather that I know that his book has been a major reason for many here and in other communities to take up very-low-carb and/or gluten-free diets, so reference and counterargumentation to his thesis and to particular studies he's cited is salient when discussing those issues, particularly in an AD context.

Now, specific to this thread:
marthaNH wrote:I have been a little flabbergasted by the other current thread here that recently seemed to argue that even mild ketosis brought on by exercise and refraining from eating was something that ought to be feared until proven safe, or something.
Stavia wrote:Excellent discussion team. I was thinking that the method that many of us use for our dietary optimisation (short feeding window, low starchy carb yet abundant leafy carb/ moderate protein hence higher fat, excercise) would result in mild ketosis in many of us who prolly don't even know they are in mild ketosis because they haven't tested. I can't see how this could be harmful and it's blinkered to lump this with a very high saturated fat very low carb diet and damn them both.
This is a very serious, root misunderstanding, and this links to my own background and set of acquired terminological connotations and the fact that I am both a recent and a relatively light reader and participant of this excellent Forum, to which I hope I will still be welcome. It underlines and makes explicit the context (and perhaps, gentle criticism) of Julie's comment that that "Anyone who KNOWS our community can easily recognize that those of us who use this strategy practice [ketosis] very differently".

Because I come in to the notion of a "ketogenic diet" out of the use of it in weight loss and purported metabolic benefits, and have interacted pretty extensively with some of the leading advocates of Atkins-type ketogenic diets in the academic community, when someone says "ketogenic diet" I do take them exactly to mean "a very high saturated fat very low carb diet" -- in particular,
We suggest the following definitions:

The ADA designates low carbohydrate diets as less than 130 g/d or 26% of a nominal 2000 kcal diet and we consider this a reasonable cutoff for the definition of a low-carbohydrate diet. Carbohydrate consumption before the epidemic of obesity averaged 43%, and we suggest 26% to 45% as the range for moderate-carbohydrate diets. The intake of less than 30 g/d [my emphasis], as noted above should be referred to as a very low carbohydrate ketogenic diet (VLCKD). The term Ketogenic Diet should be reserved for the therapeutic approach to epilepsy.
... which, of course, is also an extremely low-carb approach -- as is, importantly, the diet used in studies of "ketosis" in rodent AD models. So y'all can see why I would ASS-u-me that when people here talk about "ketogenic diets" and "sing ketosis," this is exactly what they mean. :? :oops:

And, to be extra-clear, I certainly can't object to mild ketosis resulting from "short feeding window, low starchy carb yet abundant leafy carb/ moderate protein hence higher fat, excercise, nor "concurrently employing CR, fasting, and exercise to safely create ketones ... eat[ing] enormous quantities of non-starchy vegetables and use MUFAs to stay heart healthy ... [and]interacting with top cardiologists and lipidologists in an effort to keep our members heart healthy": I do all of that myself, albeit with no particular intention of generating ketone bodies (and no, I've never tested for them -- I have and see no reason to care whether I'm producing them or not) and would encourage anyone to follow suit, whether or not they intend to "go keto" in some sense.

I hope that's clear -- and promise to be more disciplined, and monitor my assumptions, in future.

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Postby Stavia » Mon May 04, 2015 7:06 pm

Michael, I have just come from a wonderful real life meeting with Martha. One of the topics we discussed was how this forum at times is a dialogue and possibly difficult to dip in and out and pick up the thread easily. The dialogue has taken a slightly meandering course yet is mostly moving in a purposeful unified direction. But this has taken years. We are probably the only "group-mind" in the world doing this. Our conversation is by no means done as this is a rapidly moving field. I am not suprised that if you skimmed a little of our myriad posts and saw our discussion of ketosis that you misunderstood our context, purpose and underlying reasons for our dietary consensus.

A couple of responses: I do not feel the need to criticise Julie. Hope you didnt mean I did.
And it is also untrue that DrPs book has resulted in many of us following a very low carb gluten free etc. We look at all the evidence just like your CR society does.

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Re:

Postby MarcR » Mon May 04, 2015 9:12 pm

It may sometimes seem as though there is a consensus because a number of frequent posters have zeroed in on light ketosis as a strategy. I don't know what the quiet people think and do, but I can identify quite a few posters who follow their own paths. In addition to you, Michael, we have a prominent member who focuses on CR and life extension. We have someone who emphasizes real food and variation, and I perceive him to be not so far off from the inimitable ApropoE4, whom you called out a few days ago:
ApropoE4 wrote:just do what's good for the gen. pop., being more diligent about it.

We have a member who emphasizes the gut-brain connection and also thinks ketosis is too radical. I lament the loss of our two vegan posters and hope someone will step up to the plate to represent that point of view.

We have one judicious scientist who helps us assess the quality of some of the studies we discuss and reminds us occasionally that the science we're using is unsettled.

I think consensus on diet for ε4 carriers is premature and may be hazardous to our health. We have no choice but to place our personal bets each day, but I think we're safer as a group if we remain curious about and open to adopting other strategies as the science evolves. To do this, we need to cultivate courteous discussion and dissent.

Regarding Dr. Perlmutter's views, our community guidelines say, "Disagree with ideas, NOT people. This applies not only to members of our community, but also to the various expert opinions shared." The value Julie obtained personally from her relationship with Dr. Perlmutter is not relevant - it's all about courtesy. If we're to engage with and be taken seriously by people who focus professionally in this area, we have to be respectful when we disagree.

I value this forum highly for its dedication to primary sources, civil tone, and diversity of opinion. I have not seen another place quite like it. I am glad you strode into our china shop and broke some of our intellectual crockery, and I hope you'll continue along with us.
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