ApoE4 – The Ancestral Allele

For ApoE4 carriers interested in primal diets and science

More evidence on ApoE4 / HSV / Alzheimer’s connection

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Turns out there is a fair bit of study on this connection we recently reported on. Here’s another paper (gated): Herpes simplex virus type 1, apolipoprotein E, and cholesterol: a dangerous liaison in Alzheimer’s disease and other disorders. ApoE4 appears to predispose the brain to multiple weaknesses against stressors, we’ve already covered how E4s should not get hit in the head, and this HSV vulnerability is another thing to watch out for.

Written by patrissimo

May 3, 2014 at 11:19 pm

Could HSV1 be the cause of Alzheimer’s in APOE4s?

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A reader sent in this fascinating article, which offers evidence that Alzheimer’s Disease in APOE4s might be caused or partially caused by a side effect of the body’s reaction to the Herpes Simplex 1 virus (the primary cause of cold sores). Here is the paper (Note: you may need to be logged into a Google Account to see the paper embedded. Otherwise, click on the link and then download the file.)

The evidence cited includes the presence of HSV1-related DNA in the brain regions most affected by AD, that APOE4 confers an increased risk for HSV1, and direct linkage between HSV1 and the amyloid plaques and neurofibrillary tangles which are the main features of AD. If continued work validates the theory, this would not be the first time that a common virus was found to underly a major disease – consider the discovery that HPV causes cervical cancer, for which Harald zur Hausen won the 2008 Nobel Prize in Medicine, and which made it possible to create a vaccine preventing cervical cancer.

If this theory pans out, then in addition to vaccines, antivirals such as acyclovir might be able to slow or stop the progress of AD. The author’s caution that plaques in AD develop over many years, and there is no reason to think that antivirals will reverse the course of the disease. However, given the prevalence of genetic testing and the role of APOE4, perhaps long-term prophylactic treatment of identified APOE4s (perhaps also seropositive for HSV1) with acyclovir might significantly slow the development of plaques and symptoms.

Kudos to the authors, Ruth F Itzhaki and Matthew A Wozniak, of the Faculty of Life Sciences at The University of Manchester, for this innovative work.

Written by patrissimo

April 14, 2014 at 5:13 pm

ApoE4 community site: apoe4.info

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While I’ve been busy with my personal and professional life, others have (thank goodness) been gathering research so that we e4 carriers can optimize our health. The latest site is apoe4.info, of which the most notable sections are the research wiki and forums. For example, the wiki contains research on the effects of coffee, omega-3s, alcohol, turmeric, blood sugar, coconuts, and lipopolysaccharides on Alzheimer’s in e4s.

Written by patrissimo

January 29, 2014 at 9:51 pm

Posted in Research

ApoE4s Should Avoid Getting Hit In The Head

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punch to the headEven more than other people, I mean.  A fascinating new post in the Atlantic on sports & genetics, interviewing the author of a new book The Sports Gene cites an ApoE4 result I hadn’t heard of:

I’ve written about it three or four times and it never seems to get any traction whatsoever—but it’s been known for quite a while now that this gene called ApoE4. First it was discovered as a risk factor for Alzheimer’s…

It was first discovered in the mid-1990s that this gene is sort of—I don’t want to overstate it too much, but it’s like this master brain-injury recovery key. And it’s involved in all manner of recovery from any trauma, so people who get in car accidents are more likely to die, or more likely to have brain bleeding and less likely to recover, more likely to have post-injury seizures, if they have a copy of this ApoE4 gene. And now all the data today shows that the same kind of head trauma that’s in the news all the time now for sports, people with the ApoE4 gene don’t do as well with it.

One thing that was really lost in the headline when they came out with a study a few years ago about all these brain injuries in boxers and football players with Chronic Traumatic Encephalopathy, was the overrepresentation of the ApoE4 gene. So clearly, now, I think it’s indisputable that this gene is overrepresented among people who get brain damage from getting hit in the head.

Apparently there has been a lot of resistance to the idea of testing people for ApoE4 and using this information, with people offering the bogus argument that “You can’t change your genetics”. The author responds:

When I was asking doctors why we aren’t offering this to athletes, they said, “Well, basically, the thinking in the genetics community has been twofold. One: It’s just predisposition risk. You either have this disease or you don’t, and people have difficulty understanding that. And two: There’s nothing you can do about it.”

I’ve said, “Well, it’s a risk factor. You tell people that smoking is a risk factor,” and the doctors’ response is, “They can stop smoking. They can’t change their DNA.”

And I’ve said, “Yeah, but they can choose not to play football! Or not to be a boxer!”

We’re going to see a lot more of these arguments in the coming years as genetic sequencing continues to explode, so let’s all practice this response:

“Do you want to know your parents medical history? Yeah, me too. You can’t change it, but you can make choices based on it. Well, DNA is the same way. In fact, much of the value of your parent’s medical history is that it tells you about your DNA.”

Written by patrissimo

August 7, 2013 at 5:54 am

Exercise strongly preventative for E4s

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Exercise strongly preventative for E4s

From the NYT Well Blog: How Exercise May Keep Alzheimer’s at Bay, on an Alzheimer’s/exercise study that, like many new studies, included the APOE status of participants.  The key result:

For the group as a whole, exercise provided marginal benefits…barely reaching the level of statistical significance.  

That situation changed, however, when the scientists examined the results for people with the e4 gene variant. Most of those who carried the APOE-e4 gene displayed much larger accumulations of amyloid plaques than those without it.

Unless they exercised. The carriers of the gene who reported walking or jogging for at least 30 minutes five times a week had plaque accumulation similar to that of volunteers who were e4-negative. In essence, the APOE-e4 gene carriers mitigated their inherited risk for developing Alzheimer’s by working out.

We E4s are like thoroughbred racehorses – we need our daily pace around the track.  Lock us in a barn, and our brains turn to mush.  The modern lifestyle has the same effect – but it’s easily remedied.  Just go take a damn walk, or bike to work, or whatever.  It’ll be fun – and stave off the mush.

Written by patrissimo

July 20, 2013 at 5:03 am

Posted in Preventative, Research

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Omega-3s, ApoE Genotype and Cognitive Decline (Paper)

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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).

Written by patrissimo

February 21, 2013 at 7:13 am

Posted in Diet, Preventative, Research

Food collection, not production

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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

Summary begins:

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.

Written by patrissimo

December 29, 2011 at 5:03 am

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