Exaggerated ApoE4 lipid response to saturated fats?

[MarcR]

This topic of evidence for the oft-repeated statement that ApoE4's experience an exaggerated lipid response to dietary saturated fat intake arose in another thread a few weeks ago, and no one was able to respond to cdamaden's question: "could someone please post the studies that show lipid response to saturated fats for APOE4s?" I looked and didn't find compelling evidence either way. Since we often speak of this "exaggerated response" as though it's a fact, I think we should know why we think it's a fact. Which studies demonstrate this to be true?

Also, how significant is this response? Can we fill out a table like this?

Code: Select all

ApoE	Hypo	Normo	Hyper	Total
E2		?%		?%		?%		100%
E3		?%		?%		?%		100%
E4		?%		?%		?%		100%

Is it possible that we have allowed anecdotal accounts, expert opinions, and weak associative studies to close our minds prematurely on this point?

[circular]

Thanks MarcR. I volunteer you to begin a Wiki page about it It would be useful to show the non-compelling material, and then if there's something definitive it can be put in context. That would then provide a go-to page for quick evaluation of studies many of us are likely to bring up independently of one another but not have context for. Okay you can hate me now

[apod]

While restricting SFA to ~15g/d, my LDL-C measured 63 mg/dL. For me, it seems like restricting SFA clearly reduces lipids (via lower cholesterol synthesis?) I'm not sure if this is ideal, if low cholesterol has it's own set of potential problems.

While consuming lots of dairy / animal fat with an ad libitum Paleo diet, my LDL-C measured 116 mg/dL. However... while eating a lot of dark chocolate, avocados, olive oil, and nuts, with SFA up > 30g/d (occasionally brushing up near 40g/d) at 75-85% fat in my diet via nutritional ketosis, LDL-C measured <80 mg/dL -- perhaps the composition and origin of saturated fat in the context of diet+lifestyle+energy balance is of greater relevance for E4's (which doesn't seem to have much study in the medical literature) ? I've read the average american only eats around 26g of SFA/d with average LDL-C around 130 mg/dL.

I'm particularly interested in MCT's in E4's and C8 vs C10 vs C12.

Annals of Nutrition & Metabolism 2015:
https://www.karger.com/Article/Pdf/381654
"Elderly people with the highest cholesterol levels have the highest survival rates irrespective of where they live in the world." "The hazard ratio (HR) of all cause mortality adjusted for age and many potential confounding factors was calculated according to LDL cholesterol levels and revealed that all-cause mortality was essentially inversely correlated with LDL cholesterol levels in both men and women." "High LDL cholesterol levels might also be related to better cognitive function." "It seems, then, that cholesterol is not necessarily a deleterious substance after all, and may actually be a marker of healthy life and healthy organs." "An interesting cohort study in Japan has shown the beneficial effects of higher SFA intake." "SFA intake was observed to be significantly inversely associated with mortality from total stroke." "There was a trend for lower mortality from cardiovascular disease with increasing SFA intake. The notion that we should limit our intake of animal protein and fat, especially SFAs, has lost its scientific basis. Moreover, in contrast to JASG2012, the evidence from Japan indicates that we should actually increase our SFA intake." "Statin-induced reductions in th amounts of cholesterol available for hormone synthesis throughout the brain likely deteriorates memory function." "While statins lower cholesterol levels, they do not prevent CHD disease."

[MarcR]

Thanks MarcR. I volunteer you to begin a Wiki page about it It would be useful to show the non-compelling material, and then if there's something definitive it can be put in context. That would then provide a go-to page for quick evaluation of studies many of us are likely to bring up independently of one another but not have context for. Okay you can hate me now

Great suggestion, circular - no hate here! I would like to develop a wiki article format that will accommodate distillations of our collective thoughts about various unresolved issues and provide a quick way to get up to speed. Topics like Hormone Replacement Therapy E4 Women are full of useful information, but wading through hundreds of posts in threads like that one is a daunting task. This issue of E4 lipid response to SFA is straightforward and little-studied, so it should be an easy one to start with.

In the meantime, in the absence of evidence that this phenomenon exists outside the auspices of anecdote and conflicting hints in weak associative studies, I'll continue to share my skepticism regarding confident assertions here as to its existence. Note that I'm not doubting that SFA affects lipids differently from one person to another - that's easy to prove with anecdotes and is obviously true. I just don't think it has been demonstrated that the ApoE4 allele is a major factor.

[MarcR]

Thanks for chipping in with your own story, apod. Overall, it sounds like a counter-example - you're an E4 whose lipids stay low even as you eat varying levels of SFA. I'm going to resist commenting here on the other question you raise regarding whether limiting SFA can cause harm. We could always continue that discussion in this recent thread ...

[Julie G]

Is it possible that we have allowed anecdotal accounts, expert opinions, and weak associative studies to close our minds prematurely on this point?

Absolutely. I think much of our evidence re. SFA is anecdotal at this point. I’ve taken a pretty deep dive into the literature and there’s nothing definitive re. ApoE4/SFA. Per the available evidence, our population tends to have an exaggerated LDL-C (and LDL-P for some) lipid response to all dietary fat; more so than the other APOE genotypes. All APOE genotypes tend to yield lower LDL-C when switching from SFA to other fats per multiple studies like the Lyon Diet Heart Study… hence the traditional recommendation to lower SFA to improve lipids.

Stavia has very consistently recommended low SFA (high PUFA/MUFA) for our population to improve advanced lipids and glycemic markers. I’m a keen observer of lipid/diet interactions and I’ve seen many, many, many members benefit greatly from her advice. I ran my own experiment and also saw an improvement from reducing SFA. I was ketogenic (fat 60-65%) for all 3 trials. You’ll note my cholesterol is always high. I don’t think that matters (and may even be positive) in the context of low LDL-P. When I lowered my SFA to 10% of my total calories, my A1c was also the lowest I’ve ever caught at 5.0, fasting insulin 2.9, FBG- 75.

Results from 10/25/13- Highest SFA
LDL-P: 1117
HDL-P: 39.5
Small LDL-P: 115
LDL-Size: 21.2 (Pattern A)
LPIR: 5
_________
TC: 251
LDL-C: 150
HDL-C: 92
TG: 47

Results from 3/25/14-Less SFA
LDL-P: 1089
HDL-P: 39.2
Small LDL-P: 112
LDL-Size: 21.2 (Pattern A)
LPIR: <25 (Actual LPIR is NOT reported on this test)
________
TC: 210
LDL-C: 114
HDL-C: 86
TG: 50

Results from 9/10/15-Least SFA
LDL-P: 881
HDL-P: 42.3
Small LDL-P: <90 (Actual number not reported.)
LDL-Size: 21.2 (Pattern A)
LPIR<25 (Actual number not reported.)
________
TC: 221
LDL: 114
HDL: 97
TG: 49

[Stavia]

My LDL actually doesn't budge with different amounts of sat fat but I'm being prudent in my approach to sat fat. We have a whole thread discussing this "dietary saturated fat increases dementia risk".

http://www.neurobiologyofaging.org/arti ... 8/abstract

viewtopic.php?t=1153

And coupled with the fact that LDL or its various subgroups are not accurate markers of risk, I sit on the side of being prudent. I'm ignoring LDL as a step in the middle of the possibility that ???sat fat-> increased risk of dementia.
I believe the linear process of ???sat fat->LDL->dementia is not accurate

When I say I'm ignoring my LDL I don't mean that I'm ignoring my saturated fat intake. I'm still keeping it low.

[Stavia]

Marc perhaps we are not talking about the same outcomes. I'm looking at AD, perhaps you are looking at CVD and all cause mortality.
I don't want to live to 90 with dementia

[MarcR]

I ran my own experiment and also saw an improvement from reducing SFA.

By saying "improvement", aren't you begging a rather hotly debated question? That question of course is whether doing what it takes to make lipids conform to mainstream medical guidelines reduces or increases all cause mortality in the absence of insulin resistance.

And by focusing on the efficacy of your lipid manipulation techniques, aren't you knocking down a straw man? No one is questioning whether one can make lipids change by adjusting fatty acid consumption.

As we discussed in detail in another recent thread, a compelling recent study casts new doubt on the lipid hypothesis. Here's a summary from the other topic:

The 8-year study of 100,000+ people aged 50+ without preexisting diabetes or heart disease that I mentioned earlier in this thread suggests something more than "LDL is irrelevant". It's the only high-powered study I have seen that focuses on the lipids of healthy older people. I am skeptical of the studies that support the high LDL -> disease link primarily because they include so many sick people. By excluding young people and those with preexisting diabetes, heart disease, or statin prescriptions, the study shows us a cross-section of people who navigated the contemporary nutritional minefield reasonably well to 1997. The subsequent experiences of this relatively insulin-sensitive population therefore seem more relevant to my burning question - how do lipids drive mortality when insulin is low?

The fascinating answer of this study is NOT that lipids don't matter. Instead, the study suggests that lipids matter A LOT. Low lipids - those which conform to conventional recommendations - correlate with greatly INCREASED mortality. High lipids - at levels many doctors are treating with statins - correlate with greatly REDUCED mortality.

Now, it's still a prospective study, a step up from observational but well below a random controlled trial, so I don't want to leap from correlation to causation. (To my knowledge there are zero long-duration, high-powered, random controlled trials addressing this topic.) For me it just means that in a low-insulin, low-FBG, low-HbA1c, low-triglycerides world there are three camps, not two:

1. Low TC/LDL/LDL-P is best.
2. TC/LDL/LDL-P doesn't matter.
3. High TC/LDL/LDL-P is best.

If I believe that study, I will enjoy better health by ensuring that I consume enough saturated fat to get my lipids up out of the danger zone.

And finally, to all of us who think we're being prudent by taking steps to reduce our LDL, I highly recommend digging into the Karger study from which apod quoted above. It's 116 pages of meticulously cited analysis and summarization, and there are many shocking results in there. For example, check out these bits:

Liver disease seems to show the most marked association with cholesterol. Liver cancer incidence, liver cirrhosis mortality, and liver disease mortality have been found to be null in subjects with the highest cholesterol levels. [...] The multivariable HRs per 1-SD increment in total cholesterol for liver cancer were 0.45 (0.35–0.59, n = 75, p < 0.0001) in men and 0.54 (0.39–0.75, n =50, p = 0.0002) in women

A very recent study from Sweden reported 3-month, 1-year, and 5-year survival rates for 190 consecutive patients after acute ischemic stroke [16]. All three survival rates were significantly better in patients with high admission cholesterol levels (>4.6 mmol/l, >177 mg/dl) than in those with low ones (≤4.6 mmol/l).

In a multiethnic cohort of 55,300 men and 65,271 women that was followed for 15 years (1979–1993), Iribarren et al. examined the association between total cholesterol and risk of infections (other than respiratory and HIV) diagnosed in the in-patient setting [30]. Cholesterol was found to be inversely related to various infections, including all infections, in both sexes. The reduction of risk for all infections according to a 1-SD increase in total cholesterol was 8% in both sexes. This significant inverse association with all infections persisted after excluding cases from the first 5 years of follow up. These findings are mirrored in the Leiden 85-Plus Study (see Chapter 1, Section 1) where total cholesterol concentrations were measured in 724 participants with a median age of 89 years and the mortality risk from infectious disease was calculated over 10 years of follow up [31]. The higher the total cholesterol levels were, the lower the mortality from infectious disease.

[MarcR]

The neurobiologyofaging.org link is broken - I could not find the article from the bits in your post.

The other link to a prior thread offers some countervailing evidence with respect to saturated fat. Notably, some of the data was sliced by ApoE genotype. None of it appears to be as strong as the huge Scandinavian study in excluding diabetics. That's crucial to me personally because I am insulin sensitive, and I don't want to make personal health choices based on population studies of the legions of insulin resistant people who fill the world's industrialized nations today.

Because there is countervailing evidence, I'm not speaking as though any of this is settled. But on that issue of uncertainty I'm confident. The hypothesis pinning so many of our ills on LDL, the so-called "bad cholesterol", is not convincingly established as a full-fledged scientific theory. The evidence base is not solid, and conflicting studies are continuing to pile up.

I don't want to live to 90 with dementia

apod's collection of brief excerpts touched on some of the wealth that is the Karger study. Here's a longer excerpt to your point:

High LDL cholesterol levels might also be related to better cognitive function. The memory function of 193 functionally independent and community-dwelling elderly participants aged ≥80 years was cross-sectionally examined in the Key to Optimal Cognitive Aging ( KOCOA) Project, a prospective study undertaken in Okinawa, Japan [19]. High LDL cholesterol levels and low triglyceride/HDL cholesterol ratios were associated with high Scenery Picture Memory Test scores after adjustment for many confounding factors.

And here's the citation:

Katsumata Y, Todoriki H, Higashiuesato Y, Yasura S, Ohya Y, Willcox DC, et al: Very old adults with better memory function have higher low-density lipoprotein cholesterol levels and lower triglyceride to high-density lipoprotein cholesterol ratios: KOCOA Project. J Alzheimers Dis 2013;34:273–279.