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:
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.
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.
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).
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.