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

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

Postby MichaelR » Fri May 15, 2015 11:17 am

LillyBritches wrote:MichaelR - you never answered my initial query to you. I think we've all disclosed what our involvement with an ApoE4 forum is...what's yours? Are you ApoE4? If not - and this is blunt - what's your angle? Why are you posting here? Are you researching ApoE4? AD? Family member?

You've absolutely nothing to prove to me personally, but, as an e4 x 2, I'd like to place credence in your fairly detailed opinions.

So I'd like to know your gig.


I hope you'll understand, but I guard my medical privacy moderately carefully: I've never shared my actual medical data on online health discussion groups, even ones in which I've been heavily involved and despite extensive and often arcane blood tests and involvement in several medical studies.

I put it to you, with respect and understanding for your reasons for wanting to know whether I have neural tissue in the game, my status shouldn't really affect whether you put credence in my views: what the medical research says on some subject, and any given individual's ability to interpret, analyze, and communicate that information is something that should be evaluated on its own merit, irrespective of a person's background.

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

Postby Stavia » Sat May 16, 2015 12:13 am

Thank you Lilly and Michael both for your honesty. I speak only for myself when I say that if someone really cares enough to take the trouble to puzzle through the crazy complicated position we are in, listen to where we are at currently and why, and to put their energy towards helping us find the best individual paths forward for us, that person is very welcome in my e4e4 life no matter his/her apoe status.

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

Postby Juliegee » Sat May 16, 2015 10:48 am

I speak only for myself when I say that if someone really cares enough to take the trouble to puzzle through the crazy complicated position we are in, listen to where we are at currently and why, and to put their energy towards helping us find the best individual paths forward for us, that person is very welcome in my e4e4 life no matter his/her apoe status. [Emphasis Mine ;) ]


+1

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

Postby marthaNH » Sat May 16, 2015 7:29 pm

I'm ok with Michael's stance on this. Reasonable.

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

Postby MichaelR » Sun May 17, 2015 12:13 pm

Gah ... I got started on this two weeks ago, and am clearly not going to address everything I wanted to get in in the rapidly-metastasizing tangent-chasing obsessiveness of replies ... I'd like to point anyone who hasn't already seen it to my apology for giving offense on a couple of fronts, and then address just a couple of more specific points:
merouleau wrote:
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?
The topic is the subject of "Saturated and trans fats and dementia: a systematic review," which was discussed in this thread, with the studies most salient to ε4 carriers helpfully excerpted by ApropoE4. There are additional studies that are relevant, but not as direct, including:

• studies of non-Mediterranean populations' Med Diet adherence, in which the MUFA-to-SaFA ratio is one component of the composite score, but unfortunately is never disaggregated;

• the link between LDL-C (or even the relatively crude and indiscriminate total cholesterol) and AD and/or dementia, which is just as clear in carriers as in non-, and recalling that most studies show LDL-C is more profoundly elevated by SaFA in carriers than non-:
Cholesterol as a risk factor for dementia and cognitive decline: a systematic review of prospective studies with meta-analysis

... in a systematic review of 18 prospective studies[,] Follow-ups ranged from 3 to 29 years, and included a total of 14,331 participants evaluated for Alzheimer disease (AD), 9,458 participants evaluated for Vascular dementia (VaD), 1,893 participants evaluated for cognitive decline, and 4,793 participants evaluated for cognitive impairment. Compatible results were pooled using meta-analysis. Consistent associations between high midlife TC [total cholesterol] and increased risk of AD, and high midlife TC and increased risk of any dementia were found. There was no evidence supporting an association between late-life TC and AD, or between late-life TC and any dementia.
That last finding isn't very surprising, because in biologically aged people (a) total and LDL cholesterol starts to go DOWN, as the body's ability to make its own is compromised (so it's a sign of general functional decline due to aging, and not health), and (b) the effect of most risk factors for disease is reduced, because a person has already suffered a lifetime of cellular and molecular damage, and have entered into a vicious downward spiral that lifestyle changes don't affect as much.
Cholesterol and LDL Relate to Neuritic Plaques and to APOE4 Presence but Not to Neurofibrillary Tangles

... we evaluated correlations of admission [total cholesterol (TC)], low-density (LDL) and high-density (HDL) cholesterol directly with the densities of Alzheimer hallmarks—neuritic plaques (NP) and neurofibrillary tangles (NFT)—in nursing home residents (n=281).

Results: Significant positive associations of TC and LDL with NP densities were found in both the neocortex (TC: r=0.151, p=0.013 and LDL: r=0.190, p=0.005) and the hippocampal/entorhinal (allocortical) region (TC: r=0.182, p=0.002 and LDL: r=0.203, p=0.003). Associations of HDL with NP were less strong but also significant. In contrast, after adjustment for confounders, no correlations of NFT with any lipid were significant.

When subjects with any non-AD neuropathology (largely vascular) were excluded, the TC-plaque and LDL-plaque associations for the remaining "Pure AD" subgroup were consistently stronger than for the full sample.

The TC- and LDL-plaque correlations were also stronger for the subgroup of 87 subjects with an APOE ε4 allele.

Conclusions: The findings indicate that serum TC and LDL levels clearly relate to densities of NP, but not to densities of NFT. The stronger associations found in the subgroup that excluded all subjects with non-AD neuropathology suggest that cerebrovascular involvement does not explain these lipid-plaque relationships. Since the associations of TC/LDL with NP were particularly stronger in ε4 carriers, varying prevalence of this allele may explain some discrepancies among prior studies.
merouleau wrote:I'm especially interested in any studies that identify saturated fat intake as a dementia correlate in people who are not insulin resistant.
I'm not aware of studies that have looked at this specifically; I will say that I've seen arguments on this front as regards SaFA and CHD which I've not found convincing. And I would go back to ApropoE4's opener here.
merouleau wrote: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
I have not dug into that to any substantive degree, and am endeavoring to resist the urge to entrap myself in that rabbit hole ;) , but prima facie it doesn't appear that such an hypothesis is merited by the results, if you just mean that high LDL-C can be ignored if you have low TG: if it were, you'd expect the effect of LDL-C with ApoC-III to collapse upon adjustment for TG, but instead,
Another potential concern is whether a high concentration of LDL with apoC-III might just be identifying subjects with hypertriglyceridemia and mild insulin resistance. ... To address the strength of the relationship between LDL with apoCIII and CHD at different TG levels, first we added a quintile interaction term of [triglycerides*LDL with apoC-III] to the model, and its coefficient was not significant, p=0.46. Second, we computed the relative risk for LDL with apo-CIII in the participants who had normal or high TG, according to the standard cutpoint, 150 mg/dL. [I wish, of course, they had done an additional breakdown including either quintiles of TG or at least an analysis including those with TG less than (say) 75 mg/dL]. The point estimates of the relative risks were similar: 1.61 for participants with triglycerides<150 mg/dL and 1.77 for participants with triglycerides>=150 mg/dL, p for interaction=0.63. Thus the finding on LDL CIII as an independent predictor of CHD was not significantly modified by hypertriglyceridemia. ... Even though there was a significant correlation between LDL with apoC-III and plasma triglycerides (r=0.42), the association between CHD and LDL with apoC-III persisted after adjustment for triglycerides, suggesting that both characteristics may have common origins but are independently associated with CHD.
They also don't seem to have done an analysis seeing if this just collapses on total particle count.
merouleau wrote:
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.
First, to quibble a bit ;) , this wasn't a ketone-supplemented diet: they were not fed β-hydroxybutyrate and acetone ;) . Rather, they were fed "An oral ketogenic compound, AC-1202 ... a form of medium chain triglycerides (MCTs), [which] was developed to safely elevate serum ketone bodies even in the presence of carbohydrate in the diet. ... If sufficient amounts of AC-1202 are consumed, a mild state of ketosis can be induced without modification of the diet." Sure enough, "AC-1202 significantly elevated a serum ketone body (β-hydroxybutyrate) 2 hours after administration when compared to Placebo." A "ketogenic diet" is a diet that induces ketone generation; this meets the definition as well as does a very-low-carb (VLC) "ketogenic diet." I do appreciate that there's a lot of linguistic ambiguity about the use of the phrase "ketogenic diet" — cf. comments from Juliegee. IAC, whatever their metabolic triggers, the ketones per se are not different because of their origin.
merouleau wrote: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?
First, that actually wasn't the study I'd intended to link — this one was:
Effects of β-hydroxybutyrate on cognition in memory-impaired adults

... 20 subjects with AD or mild cognitive impairment consumed a drink containing emulsified MCTs or placebo. Significant increases in levels of the ketone body beta-hydroxybutyrate (beta-OHB) were observed 90 min after treatment (P=0.007) when cognitive tests were administered. beta-OHB elevations were moderated by apolipoprotein E (APOE) genotype (P=0.036). For ε4+ subjects, beta-OHB levels continued to rise between the 90 and 120 min blood draws in the treatment condition, while the beta-OHB levels of ε4- subjects held constant (P<0.009). [NB: this argues against the idea suggested by some that ε4s need MORE MCTs or other fatty acids to achieve ketosis -MR]. On cognitive testing, MCT treatment facilitated performance on the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-cog) for ε4- subjects, but not for ε4+ subjects(P=0.04). Higher ketone values were associated with greater improvement in paragraph recall with MCT treatment relative to placebo across all subjects (P=0.02).

PMID 15123336
That's a mixed result, but is clearly part of a pattern in which ε4s benefit less than non-ε4s, if indeed there is a benefit at all.

As regards the "third study" about which you asked: I don't think it affects my thesis either way, for the very reason you cite (no breakdown by genotype). If you have a study in which genotype is not analyzed, then you can get a positive result for the group as a whole if the ε4- subjects' performance improves and there is no benefit (or even a weaker decline in mental functioning) for ε4s.

To step back, I am not saying that these short-term studies slam-dunk anything: I'm saying they're lousy evidence even on the subject of treatment (they're almost all very small, and the seeming signal at 45 days in Hendersen 2009 vanished by day 90, so that it failed to meet its primary endpoint). I started this thread not to discuss treatment, but because people are talking here about using keto for prevention, for which there is no evidence at all. Invoking the available evidence in support of using ketogenic diets in AD treatment is already grasping at straws; doing so for prevention is grasping at the last hairs of a straw, and choosing not to reach for ropy vines; and ε4s heading in that direction — where the evidence, such as it is, says it's selectively ineffective — is to play a dangerous game of evidential Lucy-pulls-the-football with your own health.

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

Postby Juliegee » Sun May 17, 2015 1:04 pm

Invoking the available evidence in support of using ketogenic diets in AD treatment is already grasping at straws; doing so for prevention is grasping at the last hairs of a straw, and choosing not to reach for ropy vines; and ε4s heading in that direction — where the evidence, such as it is, says it's selectively ineffective — is to play a dangerous game of evidential Lucy-pulls-the-football with your own health.

LOL, my vote for *best sentence* on the site :D

I assume your warning is directed at a traditional ketogenic diet, as opposed to the alternative (CR, IF, exercise, reduced starchy carbs, and MUFAs) means of creating ketones that many of us practice here? If you're attacking that strategy as well, please share how YOU would address the cerebral hypometabolism that accompanies the APOE-ε4 allele?

Do you serum test your ketones, Michael? If so; I bet they're pretty similar to mine...for the same reasons. Did "Lucy pull the football on us" or are we strategically using diet/lifetyle to delay aging- the single greatest risk factor for Alzheimer's disease?

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

Postby MichaelR » Sun May 17, 2015 1:58 pm

Juliegee wrote:
MichaelR wrote:Invoking the available evidence in support of using ketogenic diets in AD treatment is already grasping at straws; ... ε4s heading in that direction ... is to play a dangerous game of evidential Lucy-pulls-the-football with your own health.
LOL, my vote for *best sentence* on the site :D
Heh. Thanks!
Juliegee wrote:I assume your warning is directed at a traditional ketogenic diet, as opposed to the alternative (CR, IF, exercise, reduced starchy carbs, and MUFAs) means of creating ketones that many of us practice here?
Yes: I addressed this here, and alluded to same in the post to which you're responding ("linguistic ambiguity about the use of the phrase "ketogenic diet" — cf. comments from Juliegee").
Juliegee wrote: If you're attacking that strategy as well, please share how YOU would address the cerebral hypometabolism that accompanies the APOE-ε4 allele?
I should say, first, that subsequent to initiating this threaad, I've realized that there's actually a pretty good reason to think that whatever ketone bodies may or may not do in AD subjects generally or ε4s in particular, they will not help with brain glucose hypometabolism and may even be counterproductive on that front. I have to elaborate later (genuinely sorry to leave this hanging!) but IAC, I don't think ketones per se are doing that, and expect that that "full-on ketosis" may even be harmful.

I'm unfortunately not sure of a good alternative strategy, tho' I think for reasons I'll also have to put off that "CR proper" (ie, not just sufficient Calories to maintain a "healthy weight") may help if done long-term.
Juliegee wrote:Do you serum test your ketones, Michael?
I don't, as mentioned in the op cit post.
Juliegee wrote:If so; I bet they're pretty similar to mine...for the same reasons.
I expect you're right.
Juliegee wrote:Did "Lucy pull the football on us" or are we strategically using diet/lifetyle to delay aging- the single greatest risk factor for Alzheimer's disease?
"Us" meaning here people doing the things you mention, that happen to lead to mild ketosis? No: there's pretty strong experimental and/or epidemiological evidence that CR, exercise, avoidance of junk carbs, and MUFA (or, more specifically, high phenolic EVOO) are protective against AD and CVD alike.

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

Postby Stavia » Sun May 17, 2015 3:46 pm

Michael, of course ketones won't help with cerebral glucose hypometabolism but they can provide an alternative fuel to top up the deficit. Have you read the work of Cunnane? I can't link, I'm on my phone in Canada. It will be on the thread I started where Julie and Martha went to New York a couple months ago for a AD conference. Please can you tell us why you refute his work?

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

Postby Stavia » Sun May 17, 2015 3:50 pm

Also, I don't know of any specific studies of "proper" CR and AD. The former is a serious undertaking with huge implications. I personally feel the proof to embark on such a course requires more rigorous evidence. And I mean specifically AD prevention evidence, hopefully that can be extrapolated to e4s. (This forum isn't a place for possible general benefits of "proper" CR.)

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Re: Ketogenic Diets for AD Prevention: a

Postby MichaelR » Sun May 17, 2015 4:42 pm

Stavia wrote:Michael, of course ketones won't help with cerebral glucose hypometabolism but they can provide an alternative fuel to top up the deficit.
This is the argument, yes — that's principally what I meant by (not) "helping," in the context of responding to previous posts, tho' as I say I think there is some reason to think that it may actually make the situation worse, whatever the mechanism(s) for any (apparent) short-term improvement in cognitive function.
Stavia wrote:Have you read the work of Cunnane?
Yes, tho' I won't pretend to have done so more than lightly.
Stavia wrote:Please can you tell us why you refute his work?
As I said, I will have to put that off for a while, but I will come back to this.
Stavia wrote:Also, I don't know of any specific studies of "proper" CR and AD.
I did say "experimental and/or epidemiological" (emphasis added): there are several studies (forthcoming) showing that CR in rodent models and nonhuman primates retards the accumulation of AD neuropathology and improves cognitive outcomes, and additional ones which suggest a reasonable basis to think that it might address the brain glucose hypometabolism issue per se.
Stavia wrote:The former is a serious undertaking with huge implications.
"Thou sayest":) .
Stavia wrote:(This forum isn't a place for possible general benefits of "proper" CR.)
Of course: I am not hear as a general-purpose CR evangelist ;) .


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