Are you afraid of eating foods high in cholesterol? Have you forsaken the pleasure of your egg breakfast?
Since the 1950’s we have repeatedly heard the message that cholesterol clogs up your arteries and causes heart disease so it may come as a surprise to hear that the evidence for this is very weak and that you do not need to worry about avoiding cholesterol in your diet, and in fact may be missing out on essential nutrients if you do so.
In the previous post I outlined the questionable link between cholesterol and heart disease and gave 6 reasons why cholesterol is essential for your existence. In this post I will give 4 more reasons and some conditions that are associated with low cholesterol. I will then give some dietary advice for those of us with the APOE4 genetic variant and for those of us who do not have this variant.
Four more reasons you need cholesterol
Cholesterol for cell membrane integrity and fluidity
Cholesterol is necessary to hold the cell membrane together and to give it the correct physical properties – the correct fluidity – to respond to hormones and other messenger signals and to allow the correct nutrients and waste products in and out of the cell in healthy amounts (1, 2, 3).
Thus it enables communication between cells which enables you to maintain balance, or ‘homeostasis’ as an integrated multicellular organism (4) rather than just a gelatinous blob of disconnected cells.
In fact cholesterol makes up 30% of your cell membranes (5) and is vital for the growth of all of your cells (6) and indeed for the development of the embryo (7). Plants, fungi and most bacteria, archaea and algae rely instead on a cell wall containing sterols other than cholesterol.
Cholesterol repairs your arteries
Cholesterol seems to act as a repair substance for blood vessel wall damage (8, 9, 10) which may come from high blood sugar (11) from a high carbohydrate diet (12, 13).
Cholesterol, mood and mental health
Cholesterol plays a role in serotonin regulation (14) and thus in mood and mental health (15).
Cholesterol for immune function
Cholesterol is now known to be vital for your immune system to fight off infections (16). Alterations are made to the metabolism of lipids and lipoproteins to support your body when fighting off an infection. These changes could, for example, ensure that cholesterol is available where needed, such as by immune cells and also to repair tissue damage from the infection.
Lipoproteins protect from toxins and support immune function
Earlier in this series I described lipoprotein as particles that transport fatty substances including cholesterol and fat-soluble micronutrients, but it is worth mentioning that these lipoproteins have other benefits for health, and that includes LDL particles which transport the so-called ‘bad’ cholesterol.
Toxins from the cell walls of some bacteria (known as gram-negative bacteria) in your gut that can enter your bloodstream and drive inflammation and disease are known as endotoxins or lipopolysaccharides (LPS).
LDL, HDL and other lipoproteins can bind with and neutralise viruses and toxins such as LPS. This binding and neutralising of LPS has been shown to protect animals from LPS-induced death.
To replicate viruses need to enter your cells where they hijack your DNA to make proteins they need as part of the replication process. HDL lipoproteins can help prevent viruses from penetrating cell walls.
Lipoproteins also help defend against parasites.
Lipoproteins also help prevent bacteria from binding to your cells and invading your tissues, in some cases by reducing toxins and invasive enzymes produced by bacteria by interfering with bacterial signalling. These changes are beneficial in the short term, but if they were prolonged the collateral damage would be a build-up of arterial plaque (17, 18).
Low cholesterol and neurodegenerative disease
So if cholesterol has all of these functions would we expect negative health outcomes when it is too low, especially when it comes to the brain where 25% of your cholesterol is found (19), although the brain is only 2-3% of your body by weight?
In the previous post I mentioned the increased risk of Alzheimer’s disease when cholesterol is low and the protective and in fact reparative effect of cholesterol on myelin sheath in multiple sclerosis.
Preliminary evidence indicates that progression of Parkinson’s disease may be slower with higher cholesterol levels (20) but a larger 2006 study found that the risk of Parkinson’s disease significantly decreased with higher cholesterol levels in women but not in men, though this may be because high cholesterol is associated with higher levels of the antioxidant CoQ10 especially in women (21). One study even showed an association between lower LDL cholesterol – so called ‘bad’ cholesterol – and Parkinson’s disease (22) and higher plasma LDL levels have also been associated with improved co-ordination and cognitive capacity in Parkinson’s patients (23). This may be partly because LDL lipoprotein particles do seem to have a protective effect against bacterial endotoxins at least in mice (24).
Low cholesterol and disease
This may also be part of the reason why LDL (as well as total cholesterol) has also been linked to improved memory scores in the elderly (25), a reduced risk of type 2 diabetes (26) and reduced mortality in most people over 60 years of age (27, 28, 29).
LDL cholesterol has also been lined with reduced mortality in asthma patients with asthma (30).
Low cholesterol is actually associated with mortality from stroke, heart disease and cancer (31). Low cholesterol is also associated with depression and anxiety (32), violent behaviour (33) and suicide (34). Women with low cholesterol are more likely to decline in their ability to perform everyday functions as they age and low cholesterol with low albumin in men is associated with an increased risk of functional decline with age (35). Low cholesterol during pregnancy is associated with preterm delivery (36) and low birth weight (37). Low cholesterol may increase your risk of dying if you suffer from septic shock (38). Tuberculosis is associated with low cholesterol levels and dietary cholesterol can be helpful in treatment of the disease (39). A prospective cohort study of 12.8 million adults found a U-shaped curve of mortality when plotted against total cholesterol levels, but the curve rises more sharply (ie mortality increases more rapidly) as cholesterol drops and rises less sharply as cholesterol rises (40).
Now I wouldn’t take the associations found in these studies as proof that low cholesterol causes these conditions but they do lend some credence, along with all of the functions of cholesterol I have outlined in this series, to the idea that a certain level of high cholesterol may in fact be beneficial.
A 1994 paper questions the approach of reducing cholesterol with a low-fat diet. It suggests, correctly in my view, that cholesterol is a red herring. Numerous studies, it says, have shown that lowering cholesterol is “as likely to increase death from cardiovascular disease as to decrease it” and “the only overall significant effect that has ever been shown is increased mortality” (41).
I would agree that lowering cholesterol is more likely to harm you than to heal you. So interfering with the body’s systems of feedback and balancing with a statin drug to block cholesterol production would be unlikely to benefit health for most people and have been shown to not even reduce all-cause mortality in those who already have a history of coronary artery disease (42). One study following 92 women aged over 60 in a nursing home over a 5 year period even found a 5.2 times increased risk of mortality in women with the lowest initial cholesterol level of 4.0 mmol/l compared with women with women with an initial cholesterol level of 7.0 mmol/l (43).
The researcher Stephanie Seneff has even published a hypothesis that cholesterol sulphate helps prevent heart disease by thinning the blood (44).
APOE4, cholesterol and saturated fat
Saturated fats have been said to increase cholesterol (and thus supposedly heart disease risk), but over the long term this may only pose a risk in those of us who have the APOE4 genetic variant, which is around 20% of us. This genetic variant affects the functioning of a protein, ApoE or apolipoprotein E, involved in lipid transport and the clearance of amyloid beta plaque in the brain.
APOE4 carriers have an increased tendency towards inflammation and an increased risk of Alzheimer’s disease and heart disease (51). In fact the risk of Alzheimer’s disease is nearly doubled in carriers with one copy of the APOE4 variant (52) and increases to 12-fold in carriers of two copies (one from each parent), with 60% of the Caucasian population with Alzheimer’s disease having at least one copy (53).
This pro-inflammatory tendency may have had an advantage in previous eras where infectious disease posed a greater risk to survival than chronic inflammatory disease, and may even now confer an advantage with preliminary evidence suggesting increased protection from cirrhosis (scarring) of the liver as a result of hepatitis C and reduced diarrhoea in children in Brazilian slums (54). Inflammation helps to fight infection and to heal injury, and the APOE4 variant predominated in our evolutionary past when we were more likely to suffer injuries and infections, with APOE2 and APOE3 variants arising much later in our evolutionary history.
As discussed in the previous post, the body regulates cholesterol levels and will produce less when less is needed, for most of us.
Some research, however, shows that saturated fat intake will increase cholesterol in APOE4 carriers but not all of the research is in agreement on this point and the effect may be small on average (55). Egg or cholesterol intake was not associated with an increased risk of coronary artery disease even in APOE4 carriers (56). However we need to remember that studies look at averages and there are other genes that may have a role when they interact with APOE4 (57).
However there is some research indicating that an increased intake of saturated fat in APOE4 carriers is associated with an increased risk of developing Alzheimer’s disease (58) and higher levels of LDL-cholesterol (59, 60), though again that does not mean that cholesterol is causing Alzheimer’s disease. Some of the research links saturated fat with Alzheimer’s disease risk in general, but lacks the stratification into APOE4 carriers and non-APOE4 carriers necessary to draw such a conclusion (61). Even though these are correlations and do not prove that high saturated fat intake is a cause of Alzheimer’s disease in APOE4 carries, it would be safer to limit saturated fat intake as an APOE4 carrier.
So at least for some individuals it seems that having the APOE4 variant may mean you need to work a bit harder to maintain optimal health, although it does not necessarily mean you will get Alzheimer’s disease. If cholesterol is increased due in part to the APOE4 and other genetic variants, as in the case of familial hypercholesterolaemia, it may be that the higher cholesterol also provided protection from infectious disease in our evolutionary past.
APOE4 has many effects in the body that could potentially be increasing the risk of Alzheimer’s disease and cardiovascular disease, including effects on blood sugar regulation, inflammation, lipid transport and clearance, vascular function, the function of neurones and synapses and effects on what are considered hallmarks of Alzheimer’s disease in the brain – amyloid-beta plaques and neurofibrillary tangles (62) and it is yet to be determined which of these factors are most at play in the development of the condition (63).
Whereas some research does indicate higher cholesterol levels in APOE4 carriers, it may not necessarily be the cholesterol causing Alzheimer’s disease and the evidence overall is not convincing, leading some researcher to wonder if Alzheimer’s disease could even be the cause rather than the effect of lipid imbalances (64).
APOE is a protein involved in lipid transport (65) and it has been found that APOE4 is linked with an accumulation of unsaturated fatty acids in glial brain cells, which support and protect the neurones in many ways, and this effect is reduced by the addition of choline, though the effects of choline supplementation on the brains of human beings with APOE4 rather than APOE4 brain cells in petri dishes remains to be studied (66).
On the other hand there is a hypothesis that I like even if it turns out to be wrong. The reason I like it is because it is based on the understanding that your genes are very unlikely to be defective.
Your genes must have had a survival advantage. Otherwise they would not have successfully propagated through so many generations. However, your genes conferred a survival advantage in a given environment. For example genes for storing more fat would and consuming more calories would surely have been very advantageous in times of food scarcity but given the current environment of food abundance your survival instinct and genetic profile may be killing you.
So coming back to the hypothesis regarding APOE4, it is noted that there is a high frequency of APOE4 in some populations that still forage for food, or where food is or has relatively recently (on the evolutionary timescale) been scarce, and it is believed that this may have helped maintain adequate levels of cholesterol in times of food scarcity and where life expectancy was lower so the age at which Alzheimer’s disease and heart disease develop might not be commonly reached in any case. It is noted also that in sub-Saharan Africans the APOE4 variant is not associated with Alzheimer’s disease and cardiovascular disease, but it is so associated in African Americans (67). However these observations might also be related to the pro-inflammatory nature of APOE4 being more important in environments where infection is a greater threat to you life than chronic inflammation.
If this hypothesis is correct could it conceivably mean that having an APOE4 variant could lead to levels of cholesterol that are higher than optimal? Perhaps that might be the case at the very end of life, but a study on subjects aged 69-71 found APOE4 carriers actually had better visual working memory than non-APOE4 carriers (68). Perhaps these APOE4 carriers had higher cholesterol (not measured in this study) and it supported visual working memory due to some of the many functions cholesterol has in the brain as discussed in the previous post. Other studies suggest improved cognitive function (or at least the aspects of cognitive function that were tested) in APOE4 carriers in earlier life (69, 70) but that may come at the expense of worse cognitive function later in life (71).
To summarise there does seem to be an increased risk of Alzheimer’s disease in APOE4 with a higher intake of saturated fat, which is also associated with a rise in total and LDL cholesterol, but it is not clear whether the elevated cholesterol plays a role in the development of Alzheimer’s disease in APOE4 carriers, or is just an innocent bystander.
APOE4 and omega-3 fatty acids
Another mechanism by which the APOE4 variant may increase risk of Alzheimer’s disease is that it has been found that APOE4 carriers burn more of the essential fatty acid DHA for energy, so that less DHA is available for it’s anti-inflammatory and neuroprotective functions. DHA is found in oily fish, but supplementing higher doses in APOE4 carriers may lead to higher levels of total and LDL cholesterol (72), though whether this would really increase the risk of heart disease and Alzheimer’s disease in APOPE4 carriers is far from certain.
Dr. Rhonda Patrick notes that APOE4 carriers respond better to DHA in fish than fish oil, and suggests that this may be because fish contains DHA bound to phospholipids and can therefore more easily cross the blood brain barrier whereas the free form of DHA is poorly transported into the APOE4 brain. Fish roe from salmon, pollock, herring and flying fish is a good source of phospholipid-bound DHA, with 38-75% of its DHA in the phospholipid-bound form. To minimise toxic burden and to save your money krill oil might be a better option, containing up to 35% of its DHA in the phospholipid-bound form. The krill oil phospholipid-bound DHA is mostly bound to phosphatidylcholine at a different position than it is in fish and roe, which makes it less likely to get broken down in the intestines to form free DHA (73).
The phospholipid that DHA is bound to both in fish roe and in krill oil is phosphatidylcholine, and I have covered research above which suggests one way in which choline might be helpful in Alzheimer’s disease prevention in APOE4 carriers, but can phosphatidylcholine formed from dietary choline intake bind with DHA in the human body to increase transport into the brain?
The one study I have found on this subject suggests increased choline intake can increase phosphatidylcholine-bound DHA in non-pregnant but not in pregnant women, though it is thought that it does so because choline supports a biochemical process known as methylation which is needed for synthesis of phosphatidylcholine in the human body, rather than by direct incorporation of the ingested choline into the phospholipid (74). This may well explain why in another study the beneficial effects on cognition of B-vitamins (which support methylation) were found to be dependent on levels of omega-3 fatty acids (75).
I speculate that one reason that results were seen only in the non-pregnant women is because pregnant women already have enough phosphatidylcholine-DHA as it is prioritised in pregnancy since the phosphatidylcholine synthesising enzyme (PEMT) that depends on methylation is up regulated by oestrogen (76) which surges in pregnancy. In the study it was indeed found that pregnant women had higher baseline levels of phosphatidylcholine-bound DHA than non-pregnant women (74).
Eggs are a very good source of choline, as are meat and fish, but APOE4 carriers could do well to reduce saturated fat intake from meat and to minimise exposure to the many toxins now found in fish. Both to support DHA transport across the blood brain barrier and for the reasons given in the research above on APOE4 glial cells, a choline supplement may in theory be supportive for APOE4 carriers, though the research to validate this advice is yet to be done.
Dietary and lifestyle advice for APOE4 carriers
So what kind of a diet and lifestyle would likely benefit you if you have the APOE4 genetic variant?
The data on dietary patterns is observational and thus cannot prove that any particular diet is best for APOE4 carriers, but the following would be the best approaches to consider given the current evidence.
A low glycemic diet is important for APOE4 carriers (77) and one approach would be a Mediterranean-style Paleo diet, without adding large amounts of additional fat other than that found already in natural form in your food, and focusing more on monounsaturated fats like extra virgin olive oil, avocado and macadamia nuts, some polyunsaturated fats and plenty of polyphenol rich deeply coloured vegetables and brassica vegetables.
By paleo what I really mean is to eat whole foods in their natural minimally processed forms and perhaps to focus more on tubers and squashes rather than grains. If you do well on legumes they are fine to eat and are a low glycemic source of carbohydrate, although some people will be sensitive to the lectins in beans. I have written elsewhere on how to balance blood sugar and for how to maximise polyphenol intake and absorption see here and here. Turmeric, ginger, rosemary and green tea are also rich sources of polyphenols that can benefit a diet for someone with the APOE4 variant, and I would strongly recommend APOE4 carriers supplement with certified polyphenol-rich organic extra virgin olive oil, even if just a teaspoon a day is all you can afford.
In an analysis of subjects of Southern Italian ancestry It has been found that carriers of one APOE4 variant have an 81% reduced chance of longevity when compared to the most common APOE3 variant when living in the United States, but when living in Italy the carriers of a single APOE4 variant had an equal chance of longevity as their APOE3 counterparts, Longevity was defined as the top percentile of lifespan – 96 years and above in men and 100 years and above in women (78).
A ketogenic diet is often recommended for Alzheimer’s disease treatment and prevention, but for an APOE4 should focus more on monounsaturated and polyunsaturated fats as described above, and potentially some shorter chain saturated fats like MCT oil (medium chain triglycerides derived from coconut oil). One study showed no benefit to APOE4 carriers with an Alzheimer’s diagnosis taking MCT oil (79), but there could be potential benefits in prevention and treatment when the MCT oil is taken in the context of a ketogenic diet to provide an alternative fuel to carbohydrate. Indeed just as the APOE4 brain seems to have impaired glucose metabolism it also seems to have improved ketone metabolism, and although as yet there is no clear consensus on the ketogenic diet for APOE4 carriers in Alzheimer’s disease prevention there are many potential mechanisms of benefit in this regard (80).
If choosing a ketogenic diet you may want to be reassured that your lipid profile is not increasing cardiovascular disease risk by working with a practitioner, although I have presented preliminary evidence here that raised LDL and total cholesterol on a ketogenic diet is not likely to increase heart disease risk in most people.
Whatever diet is adhered to, some research indicates that a higher total caloric and fat intake in associated with an increased risk of Alzheimer’s disease in APOPE4 carriers (81), which might make sense if the hypothesis that APOE4 is a genetic variant that evolved to maintain higher cholesterol levels in times of food scarcity. In any case overeating is likely to increase Alzheimer’s disease risk in APOE-4 carriers. However, this is a fine line to tread and too much restriction of calories and protein could contribute to age related muscle loss and frailty (82)
For APOE4 carriers even a moderate intake of alcohol increases the risk of Alzheimer’s disease (83, 84). Smoking also appears to be particularly harmful for APOE4 carriers, and is associated with a significantly increased risk of developing Alzheimer’s disease, as is physical inactivity (85). Regular exercise is associated with a reduced risk of Alzheimer’s disease in general, but this correlation is particularly strong in APOE4 carriers (86, 87, 88)
Humans evolved to have a long lifespan and this evolution happened when our ancestors all had two copies of the APOE4 variant. It has been proposed that a vital part of what allowed us to evolve our long lifespans despite APOE4 was a higher level of physical aerobic activity, which reduces the risk of both cardiovascular disease and Alzheimer’s disease (89). Exercise has multiple benefits for brain health as well as heart health and its importance cannot be overstated, but it is beyond the scope of this post to go into more detail here, and I have given recommendations for exercise here.
I advise APOE4 carriers to seek the support of a registered nutritional therapy practitioner, naturopath or functional medicine practitioner with an in-depth training in nutrition and an understanding of APOE4. You can test yourself for APOE4 quite easily with genetic testing that is now readily available to every individual. Cholesterol, lipoproteins and other markers of heart disease risk can also be tested by your practitioner and monitored after making dietary changes.
Cholesterol and fat recommendations for non-APOE4 carriers
Food sources of cholesterol include egg yolks, meat and especially organ meat, poultry, butter, cheese and milk. By including these foods in your diet you may reduce the burden on your liver of making more cholesterol to meet your needs. Make sure your animal produce is organic and grass-fed not overly processed and mostly cooked using low temperature methods to avoid oxidising fats and cholesterol, which does make them harmful to your health (90, 91). Cooking at 150 degrees Celsius or less reduces the formation of heterocyclic amines (92) which are likely to cause oxidative stress (93). Browning and charring of meats will increase the burden on your detoxification pathways (94) and can cause DNA damage (95). In the case of pork and poultry, however, you will need to make sure the meat is thoroughly cooked through to reduce the risk of food poisoning and do make sure to source your meat from a reliable source with good safety standards. Dairy produce is recommended only if you tolerate it well, as many of us do not.
There is no cholesterol in plant foods. If you are a vegan I advise eating saturated fat from coconut oil, palm oil, and perhaps even from cacao or cocoa products, but this is unlikely to reduce the metabolic burden of having to make all of your own cholesterol.
If you do not have the APOE4 genetic variant, you can generally eat more fat and more saturated fat within limits and provided you do not have fat malabsorption. Your practitioner can test for fat malabsorption with a stool test, or you might infer that you may have fat malabsorption if you have sticky or floating stools and if these are worse after eating fatty foods. Fat can increase the absorption of highly inflammatory endotoxins from your gut bacteria so make sure to eat good sources of polyphenols such as deeply coloured vegetables along with your fats to reduce this effect. For more information on fat in your diet please see the links below.
Familial hypercholesterolemia – genetic defect or survival advantage?
Less common than APOE4 is familial hypercholesterolemia, a genetic condition in which cholesterol is cleared from the circulation more slowly so that levels of circulating cholesterol are raised. An increased risk of mortality with familial hypercholesterolemia has been found when there is heart disease, but this may be due to another genetic variant in the higher risk individuals which leads to increased blood clotting, rather than due to the higher cholesterol levels (96).
Interestingly before 1900 familial hypercholesterolemia was associated with increased lifespan and this may have been because at that time infectious disease was the number one killer rather than chronic inflammatory disease (97). I have already mentioned cholesterol’s role in immune function but cholesterol has also been shown to be protective against bacterial endotoxins and sepsis resulting from infections (98, 99). Perhaps as gut dysbiosis and the resulting inflammation is on the increase and bacteria develop ever more resistance to antibiotics familial hypercholesterolemia might once again turn out to confer a significant survival advantage. In fact one study concludes that despite a greater risk of death from heart disease early in life, overall life expectancy is about the same as for the general population, since mortality from cancer and other causes is reduced (100). If you have familial hypercholesterolemia I advise working with a practitioner and testing more comprehensively for better markers of heart disease risk than total cholesterol.
Cholesterol: the verdict
Cholesterol provides structure to your cell membranes and allows for communication and transport of nutrients, waste and signalling molecules. It is a repair substance for your blood vessels, is vital for your immune system to fight infections and has a role in serotonin regulation and hence for mood. For most people there is no need to avoid nutrient dense animal products rich in cholesterol, such as egg yolks, meat and organ meat, poultry, butter, cheese and milk.
Are you surprised to learn about the many health benefits of cholesterol? Let me know in the comments below.
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Related posts:
10 Reasons You Need Cholesterol – Part 1
The Low-Fat Fallacy – Saturated Fat Is Good for You – Part 1
The Low-Fat Fallacy – Saturated Fat Is Good for You – Part 2
The Low-Fat Fallacy – Saturated Fat Is Good for You – Part 3
The Low-Fat Fallacy – Saturated Fat Is Good for You – Part 4
Which Fats and Oils for Optimal Health?
Blood Sugar Balance – The Key to Health, Weight Loss and Stress Reduction
The Colours That Heal You – Eating The Rainbow
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