Saturday, July 9, 2011

Apo ε4: Less UV-Triggered Vitamin D Required... Evolutionary Adaptation

** Hat tips to both Mr. Tyler Simmons of Evolutionary Health Systems Blog and a wise, flexible, strong mentor, Mr. Marc Simonson.

The 'Genetic Landscape': Apo E4 Gradient in Europe, China, India and Japan

Mr. Simonson's insights for the migration of pastoralists across Europe, originating from the fertile crescent first started my thinking (nutritional bricolage) for how the world populations have exhibited endless varieties of phenotypes and infinite genotypes (mtDNA, apo E, HFE, and thyroid/autoimmune disorders). He often says that no two people are alike unless they are IDENTICAL TWINS. Therefore, no two dietary prescriptions can be alike.

I'd strongly concur. The perfect human diet is perhaps the one suited to one's ancestral past, unique genomic profile, neolethal toxicity/damage status and metabolic goals.

The below quote comes from Lars Ulrik Gerdes work on Apo E4. He's a FANTASTIC APO*E freak! His thesis is mindblowing. I don't agree w/all of his thoughts but he has plucked through the data comprehensively and thoroughly. Regarding the ApoE4 gradient in Europe (which has also been observed in other countries and continents) 'there is a conspicuous south-to-north gradient of APOE*4 frequencies in Europe, with the proportion of APOE*4 carriers rising from only 10-15% in the south to 40-50% in the north. In contrast, the proportion of APOE*2 carriers is a little higher in Central Europe than in the south and the north. Many other genetic polymorphisms show similar south-to-north gradients in Europe, and this peculiarity of the 'genetic landscape' on our continent is presumably caused by the demic expansion of agriculture (i.e. migrations of farmers) from the Middle East that began about 10,000 years ago. The farmers first migrated westwards along the north coast of the Mediterranean sea, and later turned towards the north. Thus, the APOE*4 gradient could have arisen as an 'admixture gradient', if the apoE*4 frequency were low in the migrating populations of farmers but high in the original populations of hunters/gatherers in the north.'

Evolutionary Adaptation To Lower UV Radiation at Northern Latitudes?

Gerdes has hypothesized that apo E4 allele carriers have less of a need for UV radiation derived vitamin D due to internal adaptations to preserving vitamin blood levels and maximizing intestinal absorption from dietary sources. One of the earliest indications that this was the case was research from Willnow et al. With vitamin D binding protein and apo E protein binding sites being shared regions at the same receptor in the proximal tubule of the kidneys, Gerdes theorized that E4 may have escaped the normal urinary losses of vitamin D and its metabolites. E4 typically produce higher protein amounts of apolipoprotein E (high carb diets lower apo E protein concentrations). From Gerdes' thesis, I restated, see the below. Lard, other pastured animal fats, foraged grub, and organ meats contain substantial, rich sources of fat soluble vitamins including vitamin D. For the ancestral hunter-scavenger-forager 200,000 years ago, these fatty sources of vitamin D, K and A may have been crucial and critical for growth, maintenance and reproduction.

In migrating northward out of sun-drenched Africa, with smaller guts, less fruit/fiber/fish and subsequent lower fermentation of fiber that resulted in SCFA (short chain fatty acids like the potently anti-inflammatory butyrate), how in the world did ancestral HGs survive and have babies?

Upregulation of receptors in the gut for the fat soluble goodies from food and downregulation of the kidney's capacity to leak these fat soluble hormones, metabolites and low molecular weight proteins out...? SUPER HIGH FERTILITY, DIESEL BRAIN FUEL, AND LIPOPHILIC BULLETPROOF IMMUNITY...?

Apo E4, I believe, apparently have ALL of these amazing survivor traits.

Does APOE*4 protect against vitamin D deficiency? [p. 33 from Gerdes' thesis]

A putative association of APOE with bone metabolism has been ascribed to an impact of APOE polymorphism on the transport of vitamin K (see page 40), but it could also relate to vitamin D metabolism and embrace a very strong selection pressure. Hypovitaminosis D in childhood (rickets) causes bone deformations, which can reduce the probability of surviving to adulthood, and perhaps more importantly, can cause pelvic deformations in girls that later may cause their death during delivery under primitive conditions, and also the death of their offspring. Inadequate endogenous production of vitamin D3 can be due to insufficient dietary supplementation or reduced intestinal uptake of the vitamin, or to low exposure to sunlight (UVB-radiation). The latter can be a particular problem to people with dark skin, because melanin blocks for ultraviolet photons and thus limits the synthesis of previtamin D3 [Vogel and Motulsky, 1986].

Mourant and co-workers showed that the frequency of Gc-2-allele for the gene coding for vitamin-D-binding protein (DBP; previously known as the group-specific component, Gc, of the α2-globulins of human plasma) was high in populations living in areas with low levels of sunlight and vice versa (with some exceptions). They suggested that the distribution could be explained by means of natural selection if the encoded isoform were more efficient in binding vitamin, and so in protecting Gc-2 carriers from rickets [Mourant et al., 1976]. This may be true, although the concept has been weakened by an analysis including more detailed climatic data [Cavalli-Sforza et al., 1994].

Interestingly, a very consistent pattern appears if one correlates the frequency of APOE*4 in aboriginal peoples around the world to their skin pigmentation, while also considering the intensity of solar radiation in their habitats:

• The APOE*4 frequency is generally higher in dark-skinned humans than in humans with less melanin, and the frequency is particularly high (40-50%) for instance in Papuans, Pygmies and Khoisan, who are dark peoples and whose (recent) habitats are tropical forests where the intensity of sunlight is relatively low.

• High APOE*4 frequencies (20-30%) are also found in Saami and Inuit, who are moderately pigmented humans living in regions with low average solar radiation, and in peoples living in South American rain forests.

• Conversely, the lowest frequencies of APOE*4 (5-10%) is found among lightly or moderately pigmented humans living in areas of high insolation, i.e. around the Mediterranean Sea, in East Asia, in the southern parts of North America and in Central America.

• The APOE*4 gradient in Europe (and possible also in Japan) could be interpreted to indicate natural selection for this allele with decreasing solar radiation.

The putative advantage of APOE*4 could be related to better intestinal absorption of vitamin D (see page 30), but could also be related, somehow, to the fact that apoE and DBP both binds to megalin. This receptor plays a central
role in vitamin D metabolism, since it binds and internalizes DBP on the luminal surface in the renal proximal tubuli. The function prevents systemic loss of vitamin D through the urine and is also a step in the conversion of 25-hydroxy- vitamin D3 to the biologically active 1,25-dihydroxy-vitamin D3 [Willnow et al., 1999].

Study: Carriers of apo E4 have higher vitamin D (25OHD) blood levels compared to population controls

411 news flash...New research from last month in FASEB supports an earlier speculaton that carriers of the ApoE4 allele require less vitamin D. Willnow's research and Gerdes' theory have a line of evidence for confirmation. To prevent vitamin D deficiency and subsequent health risks (female pelvic dysplasia, fatal childbirths, growth, maturation, steroidogenesis, rickets, testosterone/progesterone production, etc), an evolutionary adaptation to recycling of vitamin D at the kidney level that raises serum vitamin D in apo E4 carriers may have occurred. The researchers state ' The novel link suggests ε4 as a modulator of vitamin D status.'

(Sorry didn't have time for tracking this PDF but if anyone can toss over would be horribly AWESOME *BIG WINK*)

FASEB J. 2011 Jun 9.
APOE {varepsilon}4 is associated with higher vitamin D levels in targeted replacement mice and humans.

Rimbach et al

The allele ε4 of apolipoprotein E (APOE), which is a key regulator of lipid metabolism, represents a risk factor for cardiovascular diseases and Alzheimer's disease. Despite its adverse effects, the allele is common and shows a nonrandom global distribution that is thought to be the result of evolutionary adaptation. One hypothesis proposes that the APOE ε4 allele protects against vitamin D deficiency. Here we present, for the first time, experimental and epidemiological evidence that the APOE ε4 allele is indeed associated with higher serum vitamin D [25(OH)D] levels. In APOE4 targeted replacement mice, significantly higher 25(OH)D levels were found compared with those in APOE2 and APOE3 mice (70.9 vs. 41.8 and 27.8 nM, P<0.05). Furthermore, multivariate adjusted models show a positive association of the APOE ε4 allele with 25(OH)D levels in a small collective of human subjects (n=93; P=0.072) and a general population sample (n=699; P=0.003). The novel link suggests ε4 as a modulator of vitamin D status. Although this result agrees well with evolutionary aspects, it appears contradictory with regard to chronic diseases, especially cardiovascular disease. Large prospective cohort studies are now needed to investigate the potential implications of this finding for chronic disease risks.

Vitamin D Dosing Revisited

For those supplementing vitamin D exogenously, care and caution for adverse effects should be monitored. Sunlight derived vitamin D can be shut off -- we have enzymes and systems that control blood/cellular levels, however for supplementation just as taking a birth control or exogenous hormone medication, what goes in, stays in. Previously I listed contraindications for vitamin d supplementation ((a) hypomagnesemia -- get mag up before supplementation because vitamin D will lower serum Mag; (b) sarcoidosis or other condition associated with elevated 25OHD or 1,25OHD3). Now I would add those with E4 should like monitor closely and avoid supratherapeutic levels which probably need to be addressed on an individual basis. With E4 there may be suggestions that intracellular 1,25OHD3 may be higher and this would not necessarily be reflected in serum levels (just like Mag levels are not, intracellular $$$$$ tests are required to accurately assess). Supratherapeutic needs to be individually defined...

So, what's an optimal, ancestral, nutrigenomically perfect serum vitamin D 25OHD and 1,25OHD3 level? I dunno. Who really knows?

Relevant Citations:

LU Gerdes Thesis HERE

The common polymorphism of apolipoprotein E: geographical aspects and new pathophysiological relations.
Gerdes LU.
Clin Chem Lab Med. 2003 May;41(5):628-31.

APOE {varepsilon}4 is associated with higher vitamin D levels in targeted replacement mice and humans.
Huebbe P, Nebel A, Siegert S, Moehring J, Boesch-Saadatmandi C, Most E, Pallauf J, Egert S, Müller MJ, Schreiber S, Nöthlings U, Rimbach G.
FASEB J. 2011 Jun 9.

Essential role of megalin in renal proximal tubule for vitamin homeostasis. Free PDF.
Christensen EI, Willnow TE.
J Am Soc Nephrol. 1999 Oct;10(10):2224-36.

Lipoprotein receptors: new roles for ancient proteins.
Willnow TE, Nykjaer A, Herz J.
Nat Cell Biol. 1999 Oct;1(6):E157-62.

Expression profiling confirms the role of endocytic receptor megalin in renal vitamin D3 metabolism.
Hilpert J, Wogensen L, Thykjaer T, Wellner M, Schlichting U, Orntoft TF, Bachmann S, Nykjaer A, Willnow TE.
Kidney Int. 2002 Nov;62(5):1672-81.

An endocytic pathway essential for renal uptake and activation of the steroid 25-(OH) vitamin D3.
Nykjaer A, Dragun D, Walther D, Vorum H, Jacobsen C, Herz J, Melsen F, Christensen EI, Willnow TE.
Cell. 1999 Feb 19;96(4):507-15.

The uptake of lipoprotein-borne phylloquinone (vitamin K1) by osteoblasts and osteoblast-like cells: role of heparan sulfate proteoglycans and apolipoprotein E. Free PDF.
Newman P, Bonello F, Wierzbicki AS, Lumb P, Savidge GF, Shearer MJ.
J Bone Miner Res. 2002 Mar;17(3):426-33.


Anonymous said...

Hi Dr. B G,

I just wanted to drop a quick note to say thanks for your previous feedback (to my comment on your other post) in which you said don't distress about being apoe4/4. It's helpful given how panic-inducing some of the information out there can be.

Again, just wanted to say I appreciate the research you do in this area, including the most recent post -- your blog is insightful and interesting to read, and seems a more grounded, thoughtful approach to understanding the apoe4 gene. Please keep up the fantastic work!


Tony Mach said...

Thanks, that was much appreciated! I will lower my Vitamin D intake for at least two weeks and see if some of my problems respond and maybe improve.

lightcan said...

Hmm, thanks dr. G

It helps understand my strange reactions. I don't know about apoe4 (but very high LDL with high sat fat), however, while supplementing vit D I notice that I need 400 mg or more of Mg and 2 g vit C to keep regular. (I suffer from constipation)

Dr. B G said...


I received the PDF (THANKS JUSTIN!!) and actually the human vitamin D levels were not reported, only the averages and the odds of correlation. Actually the blood levels may not vary as much as in the animal model in apoE3 and 2 v. apoE4.

Constipation is one of many signs of hypothyroidism... Mag is great stuff.


Anonymous said...

Hi Dr. B G,

Would you please tell me how much triglyceride DHA/EPA we should consume each day? How do we calculate it?

What if it were the ethyl ester form?

Thanks much

Dr. B G said...

Actually I'm not into the fancy fish oils... If you lack lipases (which a lot of people do and don't supplement) then these products probably have an edge for GI tract absorption. I'm not aware if the dosing is substantially different, sorry. Typically if you cannot obtain omega-3 from grassfed and safe (mercury-free, PCB-free) ocean sources than supplementing to levels that meet health status goals is advantageous. This is determined by you!

1000mg EPA + DHA = 1 g (gram)
(read the 'serving size' nutrition facts box on the bottle)

Here are my thoughts for dietary and exogenous sources, adapated from studies on ancestral origins, Dr. Sears PhD and integrative/oncology programs (with WAPF leanings, Myrna Brind integrative center at Jefferson):
1-6g/day -- maintenance
6-12g/day -- moderate to high inflammation (e.g. leaky gut, full on autoimmune disease, symptomatic ADHD, etc)
12-20g/day -- cancer, super high inflammation

Contraindications: bleeding dyscrasias, blood thinning drugs

If one burps or has reflux/repeating, this typically indicates a deficiency of gastric acid and/or pancreatic enzymes like lipases.

Flaxseed ground or oil (fresh) improves omega-3 profiles and balances long chain omega-3 in cell membranes. Overtime if high dose omega-3 is used, this supraphysiologic dosing actually depletes GLA -- which needs to be restored for balance (sesame seed, cold pressed sesame seed oil, primrose, black currant, borage, blue-green algae, etc). Most people can't convert when inflamed due to deficiencies of magnesium, zinc, and vitamins C, B3, and B6.

[U of Maryland Integrative center]

Cupcakes said...

Loving all the epo-4 activity here at your blog. This topic is so confusing it's not true! Northern latitudes more frequent, yet tropical areas high occurrence, and on and on. Question is, what do these facts have in common, and why does farming select against it1? And is it better to have an apoE4 if you are eating like a HG? All questions I would like to see answered!

From longtime reader and fan.

Anonymous said...

Hi Dr. B G,

Do you think omega 3 contributes much to the formation of lipofuscin? I'm not too keen on the thought that the extra O3 I'm taking is going to multiply the amount of age spots I get later.

Do tribal elders get age spots? There are no images of spotty tribes people that I can remember...

Thanks :-)

Dr. B G said...

Thanks Cupcakes!

After I came across the tropical latitude data on increased frequency of apoE4, then I was stumped. It could be the inverse of vitamin D access playing an important role since it is vital for hormone and steroidogenesis. Perhaps the individuals who evolved at the equator never lightened up? Never had lighter eyes? Or lighter skin? Going from smaller guts, bipedalism, and forest/canopy woodlands to sunny, tropical forests and rainforests? Pathways for upregulation of vitamin D may have occurred and in this fashion selection for maintenance for apo E4 may have occurred. The minerals still stump me but perhaps these individuals also migrated away like the Northern Euroasians from marine-based and littoral food and fauna sources? I dunno... STUMPED.

Hemochromatosis is widespread and underdiagnosed. Iron and other metal toxicity contribute to silent inflammation and even silent infections. Another adjustment to agarian-centered living!

See Vikings, hemochromatosis -- neolithic adaptation to cereal grain diet:

Dr. B G said...


Sounds like lipofuscin is related to excessive aging and the outbalancing of oxidation over anti-oxidation (AGEs related and otherwise).

I talk some antioxidants like pycnogenol and grapeseed extract when I have excessive oxidative stress (too much sunlight, lack of sleep, neolethal diet factors, etc) and my age spot(s)/laugh-lines fade immediately. I don't know why but they work well (and I am vain, can u tell). I've heard others have their freckles fade too w/certain broadspectrum antioxidants like pycnogenol and other antioxidants. Fish oil helps skin elasticity but not much for me for the wrinkle/age spot arena.

Castor oil applied on the skin is good too for this effect (but I'm too busy). I've applied a broken capsule of vitamin D/A combo onto my daughter's skin every other day and with some oral supplementation, ALL HER WARTS disappeared in 2-4wks. The pedi tried burning with liquid N2 and just created physical/emo trauma, tears and extensive SCARRING (!!).

Our topical/oral method worked flawlessly.

Silent inflammation can come from many sources. It is currently triggering epidemic autoimmune disorders, autism and chronic conditions. I'm re-reading Nakazawa's 'the Autimmune Epidemic' where she spends a great deal of time discussing mercury toxicity and other heavy metals and other very important environmental effects. These are like 100x higher in concentration in our environment and NEVER DEGRADE w/time, compared to 100 years ago. What can our baseline paleolithic-derived antioxidant status do with all this neolethal factors?? I think some have no problems but others are clearly effected. We're a wasteland of endocrine disruption as all the toxins effectly make as gender-non-specific (metallo-estrogens, xeno-estrogens, etc) and fat/inflammed. Nakazawa is great but totally neglected the antibiotic, gluten/casein/legume connections and leaky gut. Otherwise the book is mind buster b/c I think you may find it helpful. Kurzweil in his last book also discusses environmental toxins and heavy metal biological effects.

Neonomide said...

Hi G!

It seems that a finnish University (mine!) will be doing a major study on Vitamin D, check this out!

“The FIND will be a randomized, double-blind, placebo-controlled, 5-y supplementation study of the benefits and risks of vitamin D in the primary prevention of CVD and cancer among 18000 men ≥60 y and women ≥65 y. The participants will be randomized to 3 groups with 6000 in each, with daily supplementation of either: 1) 40 µg/d (1600 IU) of vitamin D3, 2) 80 µg/d (3200 IU) of vitamin D3, or 3) placebo. Compliance, use of non-study drugs or supplements, diet, development of endpoints, and CVD and cancer risk factors will be assessed by questionnaires. Blood samples will be collected for assessment of effect modification by baseline 25-hydroxyvitamin D, as well as for future ancillary studies of genetic/biochemical hypotheses.”

Looks awesome to me! What do you think? Highest dose arm 80 µg a day for 5 years is more than VITAL.

Leslie said...

I must be an exception to the rule because I am an Apo 4 carrier, and my Vitamin D test came back as less than 8 ng/ml. The optimum level is 30-80 ng/ml. In order to raise my level to 60 ng/ml, it required a DAILY dosage of 20000-24000 IU of Vitamin D3 for more than 3 months to get there. That is an abnormally high dosage of D3 for a person to take.

Dr. B G said...


You either have gut dysbiosis and/or a vitamin D SNP polymorphism where you don't metabolize vitamin D to the blood metabolite 25OHD

If you have a deficiency of bile acids, lipases (dietary fat 'cutters') from the pancreas or microvilli then either vitamin D absorption or digestion is compromised. Does that make sense.

Some people do better with the powdered vitamin D tablets, not the oil capsules in this case. If it is genetic then that may truly be the dose required (but I don't speculate so since ur said ur E4)

Please update me later?

Have you ever done a 23andme assessment of the SNPs? Have u ever done a GDX/Metametrix GI function lab?


Anonymous said...

Hi Dr. B G,

I hope you don't mind responding to old posts. :)

Regarding your last comment, if someone is without a gallbladder, would it be better to take a powdered form of vitamin D?

I've also wondered if it'd be better for them to take it on an empty stomach since there is always a trickle of bile from the liver. I would think taking the D with a fatty meal would dilute the little bile that is there.


Dr. B G said...


Not a problem..... Apparently fat digestion can still occur adequately despite post choley. I wish I knew the answer. If u try any experiment it is always prudent to retest the blood concentration at reasonable intervals, 6-8 wks initially and definitely annually.

Bile acids are very interesting and ancient. The recycling of cholesterol for our massive, complex brains and nervous systems and for hormonal internetworked systems is horrendously controlled.