Googling for the rate of APOE4 among Native Americans, I found this paper on omega-3 fats and ApoE4:
The most recent statistics indicate that dietary intake of omega-3 PUFA is insufficient in >95% of Americans. Deficits in omega-3s have been shown to contribute to inflammatory signaling, apoptosis, and neuronal dysfunction in all cause dementia, including Alzheimer’s disease. DHA (22:6[n-3]), specifically, is a critical contributor to cell structure and function in the nervous system, and a recently identified DHA-derived messenger, neuroprotecting D1 (NPD1) has been found to regulate brain cell survival and to promote non-amyloidogenic processing of amyloid precursor protein, thus protecting against Alzheimer’s disease by inhibiting formation of β-amyloid. Studies utilizing omega-3 supplementation to improve cognitive function in elders, however, have had mixed outcomes, an inconsistency which newly published research indicates is related to ApoE genotype. ApoE ε4 carriers have not been able to benefit from omega-3s. This article discusses why and what can be done to enable carriers of the ApoeE ε4 allele to receive the neuroprotective benefits of omega-3s.
The important thing for us is the dietary recommendations. Some highlights:
ApoE ε4 carriers are the canaries in the mine of the Western way of life. Individuals with this genetic heritage cannot afford the “normal” level of dietary and lifestyle insults typical of life in the modern industrialized world because the ApoE ε4 allele magnifies the risks inherent in the Western diet and lifestyle.
Despite the disproportionately high prevalence of ApoE ε4, cardiovascular disease and diabetes among Native Americans, and the Pima Indians, specifically, research examining a Native American rural population in nearby New Mexico clearly shows that carrying the ApoE ε4 allele does not increase the risk for any of these conditions in people eating a low fat diet and following an active lifestyle.
Another important point the paper makes is that while O3s provide many benefits, they are also vulnerable to oxidative damage. Depending on the body’s redox state, O3s can be neurotrophic (good for the brain) or neurotoxic (not so good).
The paper seems to conflate a low fat diet with a plant-centered, unprocessed one. While it has some great information on omega-3s, it doesn’t have much to answer other key primal / e4 fat questions like whether saturated fats are good (as in primal) or bad (because of differences in lipid metabolism for e4s).
Apolipoprotein E (APOE) allele distribution in the world. Is APOE*4 a `thrifty’ allele?
R. M. CORBO and R. SCACCHI Department of Genetics and Molecular Biology, University `La Sapienza, Rome. CNR Center of Evolutionary Genetics, Rome
Apolipoprotein E (APOE¯gene, apoE¯protein) plays a central role in plasma lipoprotein metabolism and in lipid transport within tissues. The APOE shows a genetic polymorphism determined by three common alleles, APOE*2, APOE*3, APOE*4 and the product of the three alleles diﬀers in several functional properties. APOE is involved in the development of certain pathological conditions. In particular, the APOE*4 allele is a risk factor for susceptibility to coronary artery disease (CAD) and Alzheimer’s Disease (AD). In the present study we analyzed the APOE allele distribution in the world…
Some key messages:
It appears from our analysis that the APOE*3 allele is the most frequent in all the human populations and that its frequency is always negatively correlated with that of APOE*4, indicating that the ancestral allele was progressively substituted by the new allele carrying the 112arg!cys mutation. The highest APOE*3 frequencies are found in populations with a long-established agricultural economy (Gerdes et al. 1996) such as those of the Mediterranean basin (0.849±0.898) or East Asia (0.82±0.87). It is possible that the metabolic properties of the E3 isoform proved to be particularly advantageous in the transition from food collection to food production. At present, the frequency of APOE*4 within all the major human groups remains higher in those populations…where an economy of foraging still exists, or food supply is now or has until recently been scarce, sporadically available or qualitatively poor. Under these environmental conditions, carrying the APOE*4 could be still useful. For example, most of these populations have lower plasma cholesterol levels than those observed among Western countries. Since APOE*4 is associated with both a higher absorption of cholesterol at intestinal level, and higher plasma cholesterol levels, individuals carrying it would be favoured because this allele could help in rebalancing cholesterol levels which would otherwise be too low (Scacchi et al. 1997)
Hopefully this just means we should eat primal, I totally don’t want to eat a low cholesterol diet. As we can see below, it’s clearly a gene-environment interaction that leads to high levels of heart disease (CAD) and Alzheimer’s (AD) for APOE4s, because the developing world has more E4s yet far less CAD & AD. There are two hypothesis for what the environmental aspect of the Western lifestyle is which triggers these problems, one of which is good for us & one is bad.
The first is that it’s the Western diet & low-activity lifestyle, which means by eating primal, we’ll be fine. The second is that since CAD & AD happen when old, it may just be that longer Western lifespans allow the disadvantages of E4 to develop. The key data for us, then, is to find some high E4 populations, and see what their lifespans are & whether those individuals who live into their 70s & 80s get CAD & AD.
APOE*4 could be considered a `thrifty’ allele based on certain functional properties it exhibits and on its distribution among human populations. At present it is considered a susceptibility factor for CAD and AD, diseases highly prevalent in Western populations but far less so or completely absent in developing countries, where instead APOE*4 is most frequent. Since both CAD and AD are complex diseases whose occurence depends on gene-environment interactions, exposure of APOE*4 to contemporary environmental conditions may have rendered it a susceptibility allele for CAD and AD. One of the new environmental conditions favouring this change could be the western lifestyle in general, with its diets rich in carbohydrate and fat, but poor in fibre intake, along with reduced physical activity. Longer average lifespans and aging populations count as two more environmental factors particular to the developed countries, since both the diseases occur in adult and advanced age.
It isn’t very primal, but the Track Your Plaque blog – which generally advocates a fairly primal diet – says that APOE4 fat metabolism responds poorly to saturated fat:
I witness spectacular results restricting carbohydrates, both in the office as well as in my online experiences, such as those in Track Your Plaque. Of course, the diet I advocate is not just low-carb; it starts with elimination of wheat (for a long list of reasons). So the diet is wheat-free in the setting of low-carbohydrate.
But there’s one group of people who can experience unexpected effects with this diet: The 25% of people with apoprotein E4….I hate apo E4. I hate apo E4 because it means I’ve got to dust off the nonsense I used to tell patients about cutting their fat, cutting their saturated fat. But that’s what apo E4 people have to do. But it doesn’t end there.
Apo E4 people also typically have plenty of small LDL particles triggered by carbohydrates. Put fats and carbohydrates together and you get an explosion of small LDL particles. Remove fats, small LDL goes down a little bit, if at all. Remove carbohydrates, small LDL goes down but total LDL (mostly large) goes up. The large LDL in apo E4 does seem to be atherogenic (plaque-causing), though the data are fairly skimpy.
So apo E4 creates a nutritional rock and a hard place: To extract full advantage from diet, people with apo E4 have to 1) go wheat-free, low-carb, then 2) not overdo fats, especially saturated fat.
It still gives me the creeps to tell an apo E4 person that they’ve got to watch their fats, worse than watching Starsky and Hutch reruns.
Information like this will help us narrow in on the optimal diet for our ancestral allele. I’d like to learn more about what kinds of fat are healthy for E4s, since low-fat, low-carb would mean high-protein, and research suggests that too much protein is hard on the body and not good for life-extension in general. And too much carbs is not good either (unless perhaps it is root vegetables). Fat is the best macronutrient – so which fat is best for us? I posted a comment, we will see if the good doctor responds.
One of the things we’ll probably do a lot here is to summarize relevant papers. For a dose of optimism, let’s start with a paper about the advantages of E4, Better Memory and Neural Efficiency in Young Apolipoprotein E ε4 Carriers. Researchers are interested in this topic because E4 (the ancestral allele) still sticks around at significant frequencies in all populations – it hasn’t been totally displaced by the more recent E2 and E3. So unlike a genetic disease caused by a rare mutation, where one really can think of the gene as “a disease gene”, it seems likely that ApoeE4 has some benefits, and there is a hypothesis that it is being maintained by “balancing selection”.
The apolipoprotein E (APOE) ε4 allele is the major genetic risk factor for Alzheimer’s disease, but an APOE effect on memory performance and memory-related neurophysiology in young, healthy subjects is unknown. We found an association of APOE ε4 with better episodic memory compared with APOE ε2 and ε3 in 340 young, healthy persons. Neuroimaging was performed in a subset of 34 memory-matched individuals to study genetic effects on memory-related brain activity independently of differential performance. E4 carriers decreased brain activity over 3 learning runs, whereas ε2 and ε3 carriers increased activity. This smaller neural investment of ε4 carriers into learning reappeared during retrieval: ε4 carriers exhibited reduced retrieval-related activity with equal retrieval performance. APOE isoforms had no differential effects on cognitive measures other than memory, brain volumes, and brain activity related to working memory. We suggest that APOE ε4 is associated with good episodic memory and an economic use of memory-related neural resources in young, healthy humans.
So basically, they watched the brains of people with various APOE alleles while they did some brain tests. The allele made no difference to overall performance, the big difference came in the efficiency episodic memory (memorizing facts from the recent past, as opposed to working memory, which is based on how much you can hold in your head at any one time). Specifically, there was an interesting effect where E4s used less energy (less brain activity) each time they learned a repeated fact, whereas E2s and E3s used more energy each time. They all used the same amount of energy the first time, and they performed equally at remembering the fact, but E4s needed less energy to reinforce the memory each time while E2s and E3s needed more.
The paper has a good summary in the intro of what’s known about ApoE4:
Although the frequency of the APOE4 allele is low in humans (15% in Caucasians), studies in primates suggest that it is the ancestral allele (Finch and Sapolsky 1999). The common (75% in Caucasians) and uniquely human APOE3 allele appeared as a mutation, and its frequency increased during human evolution (Finch and Sapolsky 1999). Because the APOE4 allele has been related to several deleterious biological effects, the question arises why it existed in the first place (Finch and Sapolsky 1999). From an evolutionary point of view, a possible advantageous effect of the APOE4 allele in childhood and early adulthood could explain its existence and further persistence in humans. Support for this notion comes from studies where APOE4 has been associated with higher IQ scores (Yu et al. 2000), a higher educational level (Hubacek et al. 2001), a reduced cardiovascular response to experimentally induced stress (Ravaja et al. 1997), and a protective effect against spontaneous abortion during embryogenesis (Zetterberg et al. 2002) and against perinatal death (Becher et al. 2006). Advantageous effects of the APOE4 allele have also been found for memory-related functions in young animals. Hippocampal long-term potentiation (LTP) was enhanced at a young age in knock-in mice lacking mouseAPOE but instead expressing human APOE4 (Kitamura et al. 2004). This LTP enhancement was age dependent and disappeared in adult knock-in mice. Moreover, APOE4, but not APOE3, stimulated the transcriptional activity of cyclic adenosine 3′,5′-monophosphate response element-binding protein (CREB) by activating the extracellular signal-regulated kinase (ERK) cascade in rat primary hippocampal neurons (Ohkubo et al. 2001).
It’s worth remembering that almost all evolutionary changes involve tradeoffs, because any simple change that’s a pure advantage will quickly get discovered and spread by evolution. Everything left involves tradeoffs, where the optimal balance shifts as the environment changes. The novel ApoE alleles E2 & E3 have increased in number over the last tens of thousands of years because of their net benefit – in one theory, the main benefit is the longer lives they allow by reducing heart disease and Alzheimer’s, which became important as grandparents took on an increased role in child-rearing. Here we see one of their costs: increased energy use in episodic memory storage for the young.
This is a new blog for carriers of the Apolipoprotein allele ε4, as well as researchers and others interested. Our perspective is:
- Practical – interested in taking action to maximize our health.
- Primal – we believe that selectively emulating aspects of the hunter-gatherer lifestyle, such as diet, is a powerful general strategy for health, and that this is especially true for us ApoE4s, since it’s a pre-agricultural allele.