Ketogenic Diets for AD Prevention: a "Large [and Unwise] Bet"

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MichaelR
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Ketogenic Diets for AD Prevention: a "Large [and Unwise] Bet"

Postby MichaelR » Fri May 01, 2015 12:47 pm

All:

Following from a sub-thread in the discussion on the New York Academy of Science Conferrence on The Role of Nutrition in Dementia Prevention and Management by two highly intelligent Forum participants:
ApropoE4 wrote:The answers [about ketosis and saturated fat] are in turn: 1. nobody's got a clue. 2. in light of (1), just do what's good for the gen. pop., being more diligent about it.
(The Board software will only let me embed 3 quotes within each other, so what follows all proceeds from Stavia's response to that initial thesis):
Stavia wrote:
ApropoE4 wrote:
Stavia wrote:If the glucose metabolism story is a significant issue for us, then not chasing ketosis as an alternate fuel might have permanent conesquences. [...] Of course there is no certainty, but IMO some yes/no decisons need to be made.
I hear your cynicism ApropoE4, but I dont want to have regrets that I didnt carefully consider options, including long term consequences either way, without bias.

It's not cynicism, but in the presence of high uncertainty you need to avoid large bets. As far as I know there is no evidence to support a ketogenic diet to prevent, cure, or delay AD. There is some evidence that it helps manage symptoms when the disease is already active. So it's not that there isn't certainty, but there isn't even any indication of probability

I hear you Apropo, and I agree re large bets. I dont make large bets.
I would suggest to all concerned that spending decades on a ketogenic diet in the current state of the evidence is a very large — and unwise — bet. If you are trying to prevent AD, you're talking about spending literally a decade or more in a ketogenic state. There is simply no evidence at all on what the long-term health consequences of doing this are: no trials of ketogenic diets have lasted more than a few months (the longer-term low-carb diet trials all intentionally move people off of full-on keto (Atkins "Induction" phase) to a more moderate-carb maintenance approach (Atkins “Ongoing Weight Loss”)), and very few people in the population practice keto diets for any length of time at all, so there is zero prospective epidemiology on long-term outcomes.

Indeed, the study that keto advocate David Perlmutter disingenuously cites as supporting his recommendations(4) does no such thing, but rather supports a moderately low-carb, Zonish 20: <47 : 37% protein:carb:fat profile (Table 2), with the biggest difference amongst extreme quantiles being low intake of sugar, with which everyone from Ornish to Atkins and the Dietary Guidelines for Americans all endorse. (More dissection of Perlmutter nonsense on the CR Society Listserv, whose Archives are unfortunately down once again just at the moment).

It's possible that at least some Paleo and recent hunter-gatherer populations may have spent much of their lives in a ketogenic state, but we have no data on their risk of age-related dementia: life expectancies were simply too short for AD to have been an outcome that could be sampled (if indeed it could be diagnosed, or evaluated in fossils). (Paleo enthusiasts will say that the life expectancy thing is a red herring, as you have to consider life after censoring out child and infant mortality; even when you do this, life expectancy for recent h-gs has been in the low fifties.(1,2) Similarly, (3) reports that "Up until age 15 or so, hunter-gatherers experience death rates >100-fold higher than in today’s Japan and Sweden, and hunter-gatherer mortality remains >10-fold higher for the entire life span." Plus, Paleo/h-g populations got a hell of a lot of physical activity, which sure seems to be protective against AD and possibly disproportionately so in ApoEε4 carriers, so attributing any findings of low dementia rates, if such data existed, to diet (let alone diet-induced ketosis specifically, rather than low sugar, lots of veggies, etc) would be to pick one data point out of a shotgun scatter).

And even the limited evidence to which ApropoE4 alludes, suggesting that a ketogenic diet may help people with existing AD (not, again, to prevent or delay AD onset) finds that ketogenic diets seem to be ineffective precisely in ApoEε4 carriers:
http://www.nutritionandmetabolism.com/content/6/1/31
http://www.biomedcentral.com/1471-2350/12/137
http://www.neurobiologyofaging.org/arti ... 2/abstract

And remember, one can't make the risk:benefit calculation for keto in a vacuum: one must include the opportunity cost of more evidence-based dietary patterns that seem essentially incompatible. Notably, there is plenty of evidence for the protective effects of the decidedly non-ketogenic Mediterranean diet. Olive oil, most vegetables, fish, wine, and low sugar intake are keto-compatible, but legumes, dairy (other than cheese), fruit, and minimal land-based meat do not.

Similarly, there is substantial evidence that higher saturated fat intake increases one's odds of dementia. It's of course possible to devise a keto diet with low SaFA intake, but it is rather difficult, and certainly incompatible with either use of MCT oil, coconut oil (don't get me started ...), or reliance on standard low-carb cookbooks and blog recipes. (In fact, if you're shooting for 70% fat, even if you had zero fat in your diet except for EVOO, you'd already be at 7% of Calories from SaFA, which the AHA's SaFA limit; if you eat any meat, cheese, coconut oil, etc at all, you'd be over the top).

References
1: Hillard Kaplan, Kim Hill, Jane Lancaster, and A. Magdalena Hurtado (2000). A Theory of Human Life History Evolution: Diet, Intelligence and Longevity. Evolutionary Anthropology. 9 (4): 156–185. doi:10.1002/1520-6505(2000)9:4<156::AID-EVAN5>3.0.CO;2-7
http://www.unm.edu/~hkaplan/KaplanHillL ... lution.pdf

2: Gurven, M. and H. Kaplan (2007). Longevity among Hunter-Gatherers: A Cross-Cultural Examination. Population and Development Review 33(2): 321-365. E-ISSN: 17284457
http://www.anth.ucsb.edu/faculty/gurven ... 007pdr.pdf

3: Burger O, Baudisch A, Vaupel JW. Human mortality improvement in evolutionary context. Proc Natl Acad Sci U S A. 2012 Oct 30;109(44):18210-4. doi: 10.1073/pnas.1215627109. Epub 2012 Oct 15. PubMed PMID: 23071331; PubMed Central PMCID: PMC3497824.

4: Roberts RO, Roberts LA, Geda YE, Cha RH, Pankratz VS, O'Connor HM, Knopman DS, Petersen RC. Relative intake of macronutrients impacts risk of mild cognitive impairment or dementia. J Alzheimers Dis. 2012;32(2):329-39. doi: 10.3233/JAD-2012-120862. PubMed PMID: 22810099; PubMed Central PMCID: PMC3494735.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3494735/

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Julie G
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Re: Ketogenic Diets for AD Prevention: a "Large [and Unwise] Bet"

Postby Julie G » Fri May 01, 2015 3:11 pm

Michael, you make many good and valid points; ALL of which we've discussed here in great detail. I would go so far as to say that we currently have NO members (maybe one?) who are practicing a ketogenic diet that is high in SFA.

The vast majority of us, who do use ketosis to address the cerebral hypometabolism/mitochondrial dysfunction, that accompanies the E4 allele, do so via- caloric restriction, fasting, exercise, some starchy carb restriction, primarily using MUFAs. We are keenly aware of our propensity for higher lipids and encourage members to track advanced lipids and a host of other biomarkers often.

I’m a patient of Dr. Perlmutter's who HAS employed mild ketosis as a part of my overall strategy and have experienced greatly improved cognition and overall health as a result. By using the tactics described above, I've been able to keep my CAD/CVD risk low. Many members experience improved cognition with ketosis; some don’t. We’re working hard as a community to juggle and address the multiple health implications of the APOE e4 allele.

MichaelR wrote
My very first stumble across the ApoE4.info website was a blurb quoting David Perlmutter as if he were some kind of authority on anything but the art of making duck calls look like medical information, and I learned that one of the early movers here is (or was at the time) an enthusiast for his ideas; I had half-expected to witness a tribal pile-on of denunciations ...

Help us understand why you repeatedly come to the site to bash Dr. Perlmutter? As I explained to you in early 2014, that quote “DNA is not your destiny” was chosen for it's hopeful message; not to advocate Dr. Perlmutter’s approach. To placate you, we removed that quote with Sir Francis Bacon's “Knowledge is Power.” I happen to love both for our site. Please feel free to make any suggestions for another site quote that would prefer to see.

As a non-E4 carrier, I totally understand why you DON'T spend time here getting to know our community and the struggles we face. Perhaps consider doing so; we'd surely benefit and you may learn a few things too.

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Postby Stavia » Fri May 01, 2015 3:24 pm

Thank you Michael for this frank discussion. You have given us food for thought and taken a lot of trouble to do so.

There may be a middle road ( those who know me will understand my philosophy on this as the safest place to stand in a landscape of uncertainty) in that the researcher at the NY conference (on my phone in the airport at San Francisco so cant link) suggested that 0.3 to 0.5mmol/l ketones may be enough. This actually happens just naturally as a secondary effect to me with only 35 to 50% fat, less than 7grams sat fat and mild CR (1100 to 1200 cals). I can't see how this can be harmful. I wouldn't have even known if I hadn't tested.

Those of us who chase deeper ketosis feel really good on it. That's an important factor too.

I do hope that we come to a better understanding of this particular issue for us in the near future. A decade of uncertainty feels quite scary.

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Re: Ketogenic Diets for AD Prevention: a "Large [and Unwise] Bet"

Postby RichardS » Fri May 01, 2015 3:52 pm

I believe that MichaelR has done a good job characterizing the literature on ketosis for prevention and treatment of AD. I've revisited this literature several times and have been disappointed at how little clinical evidence there is. There is no epidemiological ketosis research as no well-studied populations live in ketosis for years.

I have no doubts that many have felt benefits being on a ketogenic diet, but like MichaelR, I don't believe we can call on the current state of the ketosis literature to support AD prevention. Even restricting to AD treatment gives us only a couple of small human trials last I checked. I think only one of them was actually a randomized one, and it was funded by the company that provided the MCT supplements used.

For an interesting take on the potential downsides of a ketogenic diet, keep an eye out for Dr. Sarah Ballantyne's follow-up to her Paleo f(x) talk. http://www.thepaleomom.com/2015/04/tpv- ... diets.html She promises a very detailed blog post to include all the scientific reference used for her talk. I've been following her for years and have been impressed with her scientific background and intellectual integrity. The podcast is worth a listen, but it is over an hour long.

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Re: Ketogenic Diets for AD Prevention: a "Large [and Unwise] Bet"

Postby LAC1965 » Fri May 01, 2015 5:34 pm

As someone who literally can’t think when out of ketosis (I need a blood ketone level of slightly over 1 to function), I don’t see any other option at this point. If I’m not consistently in ketosis I can’t work, etc. This is extremely scary (like having your brain ripped away, almost like a switch has been flipped, with a drop in ketone level), and I am very worried about my future. So I understand the concerns about lack of evidence and risk, but I really feel like I don’t have a choice. The effects of a ketogenic diet are that significant for me. I’m not sure how I would approach this if my brain still functioned effectively on glucose. I suspect I would be a bit more moderate. In any case, there may be some people for whom a ketogenic diet really is critical.

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Re: Ketogenic Diets for AD Prevention: a "Large [and Unwise] Bet"

Postby Ski » Fri May 01, 2015 6:40 pm

Thats just it. No matter what the literature says, if something works for you and has obvious drastic improvements, thats what you gotta go for, regardless.

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Re: Ketogenic Diets for AD Prevention: a "Large [and Unwise] Bet"

Postby MarcR » Fri May 01, 2015 6:52 pm

MichaelR wrote:Similarly, there is substantial evidence that higher saturated fat intake increases one's odds of dementia.

Michael, I wonder if you would be willing to share one or more references for this statement? I'm especially interested in any studies that identify saturated fat intake as a dementia correlate in people who are not insulin resistant.

On the CVD/CHD front, I would love to know what you think of this discussion of ApoC-III. I think the paper of note provides a plausible argument for assigning different risk profiles to these scenarios:

high LDL + high triglycerides
high LDL + low triglycerides
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Re: Ketogenic Diets for AD Prevention: a "Large [and Unwise] Bet"

Postby MarcR » Fri May 01, 2015 11:49 pm

Ski wrote:Thats just it. No matter what the literature says, if something works for you and has obvious drastic improvements, thats what you gotta go for, regardless.

Totally agree. The epidemiological and observational studies just give us a basis for calculating odds to place a bet when we don't know what works for us. The aggregate odds ratios tell us how likely it is that we'll win our bets. Placing a bet as per overall population odds when we already know from direct experience what works for us would be crazy!
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Re: Ketogenic Diets for AD Prevention: a "Large [and Unwise] Bet"

Postby Stavia » Sat May 02, 2015 12:04 am

merouleau wrote:
Ski wrote:Thats just it. No matter what the literature says, if something works for you and has obvious drastic improvements, thats what you gotta go for, regardless.

Totally agree. The epidemiological and observational studies just give us a basis for calculating odds to place a bet when we don't know what works for us. The aggregate odds ratios tell us how likely it is that we'll win our bets. Placing a bet as per overall population odds when we already know from direct experience what works for us would be crazy!



Seconded. There are too many possible genetic combinations to be dogmatic. Its as complex IMO as chaos theory or economic theory. If you feel horrible and your markers deteriorate, don't do it. And the flip side too. Bottom line.

And Julienne sister, I vote for "knowledge is power". It's a no-brainer as we call it here. Excuse the flipped nerdy pun.

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Re: Ketogenic Diets for AD Prevention: a "Large [and Unwise] Bet"

Postby MarcR » Sat May 02, 2015 10:17 am

MichaelR wrote:And even the limited evidence to which ApropoE4 alludes, suggesting that a ketogenic diet may help people with existing AD (not, again, to prevent or delay AD onset) finds that ketogenic diets seem to be ineffective precisely in ApoEε4 carriers:
http://www.nutritionandmetabolism.com/content/6/1/31
http://www.biomedcentral.com/1471-2350/12/137
http://www.neurobiologyofaging.org/arti ... 2/abstract

Michael, the first two studies pertain to ketone-supplemented rather than ketogenic diets:
Subjects were on a normal diet
Subjects were not asked to change their diets

A ketogenic energy supply and consumption pattern that stimulates endogenous ketone production through some combination of fasting, caloric restriction, exercise, restriction of high-GI carbohydrates, and moderation of protein consumption seems likely to have different health effects.

I don't have access to the third study, which does study ketogenic nutrition rather than ketone supplementation, but from the abstract I see no indication that the study considered E4 status. (If it does, I think at n=23 it is underpowered.) Its conclusions appear to undermine your thesis - what am I missing?
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