Is ApoE4 Neanderthal?

[SunnySky]

Sorry, Mike. I wasn't clear.

This IS what we have:

My husband is 4/4 with 288 Neanderthal variants; which is more than 69% of 23&me customers.

Our daughter is APOE4 (heterozygous) with 303 Neanderthal variants; which is more than 87% of 23&me customers.

I do not have APOE4 and have 296 Neanderthal variants; which is more than 80% of 23&me customers.

[circular]

If ApoE4 is Neanderthal, then it seems like it would be useful to know what they ate. From the research, it looks like they ate pretty much whatever they could. In Northern climates, it was more meat, and in the south, more vegetables. And insects even. I'm not seeing anything about tubers though. It appears that they ate a VERY low carb diet for the most part, with seasonal fruit.

On the other hand, since E4 is the ancestral allele in all primates (I think, right???), then there would have been a wide variety of both diets and food/fast cycles experienced by E4 populations. I don't think the small amount of Neanderthal DNA in us could be suggestive of how we should eat, and a closer look at what Neanderthal genes are being found in DTC testing suggests some of the other possible Neanderthal variants one might acquire may have more specific significance for us ...

Looking at my results from two companies:

23andMe

At 23andMe I have 294 Neanderthal variants, and they add: 'You have more Neanderthal variants than 78% of 23andMe customers. However, your Neanderthal ancestry accounts for less than 4% of your overall DNA.'

Insitome

Insitome, via the Helix exosome testing platform, says I have 1.8% Neanderthal but doesn't say how many variants that includes. However, they go on to say for a small subset of SNPs whether you have the Neanderthal or Modern variant and then provide text explanations:

Pigmentation
Sun Damage Repair
Torso Shape
Learning (mostly TANc1) +
Fat Storage
High Altitude Adaptation
Interpreting Immune Signals (STAT2, Neanderthal is better) *
Pathogen Recognition (TLR1-TLR6-TLR10 cluster, Neanderthal is better) *
Viral Immune Response (OAS genes, Neanderthal is better) *
Muscle Growth and Development

+ Learning is the only set of Neanderthal genes reported that I inherited from Neanderthals, but it's a rather large set compared with the other categories, so it placed me at the higher end for # of Neanderthal genes. 'These are primarily associated with visual learning, long term memory and cognition'. I'd need time for a deep dive to better understand this result.

* The Neanderthal immune SNPs that I did not inherit may provide a window into why my immune system struggles and I'm Type 3 toxic in Dr. Bredesen's approach. I have the modern version, so I didn't inherit three immune advantages from the Neanderthals. It would be interesting for Dr. Bredesen to look not only at the HLA haplotypes for mold and pathogen susceptibility, but also to look at the Neanderthal immune SNPs. It doesn't provide a solution (inject Neanderthal versions, something like an E4 corrector???), but it might help identify people who are susceptible to Type 3 so protective protocols, whatever they may be, can be encouraged.

[mike]

Sorry, Mike. I wasn't clear.
This IS what we have:
My husband is 4/4 with 288 Neanderthal variants; which is more than 69% of 23&me customers.
Our daughter is APOE4 (heterozygous) with 303 Neanderthal variants; which is more than 87% of 23&me customers.
I do not have APOE4 and have 296 Neanderthal variants; which is more than 80% of 23&me customers.

SunnySky, yes I understood you. It was me that was probably unclear. I'm also not a genetic or Neanderthal expert in any way, so I could be completely off-base. I'm thinking that you are taking a sample of 3 and trying to show there is no correlation between E4 and % Neanderthal. And I would argue that we need a larger sample size. My remark about probability was just that the odds go up to get a particular Neanderthal variant as your % of total Neanderthal variants goes up. But just because the odds go up, doesn't mean that it will happen.

[mike]

On the other hand, since E4 is the ancestral allele in all primates (I think, right???), then there would have been a wide variety of both diets and food/fast cycles experienced by E4 populations. I don't think the small amount of Neanderthal DNA in us could be suggestive of how we should eat, and a closer look at what Neanderthal genes are being found in DTC testing suggests some of the other possible Neanderthal variants one might acquire may have more specific significance for us ....

Circular, thanks for responding. I did a very early 23andMe, and haven't looked at it in years. I just sent in a new sample to get tested using their new routines. I look forward to getting the results, but I did not understand much of what you presented...

My basic argument is that yes, everyone started with E4. Neanderthal left Africa and then became genetically isolated for a period. Man in Africa learned to cook tubers after Neanderthal left. Before tubers, the only carbs man had was seasonal fruit, now they had access to year-round carbs. E3 variant appeared, allowing man to better utilize these carbohydrates, and then spreads rapidly to most areas, except for those that are genetically isolated. When man comes out of Africa 45,000 years ago and meets up with the Neanderthal, they have a dietary advantage. As far as I can find, the highest % of Neanderthal DNA occurs in Northern Europe, which would support the Neanderthal E4 theory.

[Verax]

The only data I could find online about Neanderthal ApoE4 is in the paper by McIntosh et al. (2012) "The Apolipoprotein E (APOE) Gene Appears Functionally Monomorphic in Chimpanzees (Pan troglodytes)" PLoS One. 2012; 7(10): e47760.
doi: 10.1371/journal.pone.0047760 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3480407/ where alleles for rs429358 and rs7412 are "unknown." However, Denisovans according to this study were E4/E4, as were all humans (uniquely--chimps are not polygenic) until 300,000 to 200,000 years ago, when E3 and E2 arose. Currently earliest fossils of Neanderthals (derived from Homo erectus) in Europe are dated at 430,000 years ago, and thereafter Neanderthals expanded into Southwest and Central Asia, until they went extinct some 40,000 years ago.

Homo sapiens and the other two humanoids have intermixed periodically since (outside Africa) in a trellis-like history. A paper in Science (behind a paywall) "The phenotypic legacy of admixture between modern humans and Neandertals" links Neanderthal DNA to hypercoagulation, actinic keratosis, depression, and nicotine addiction, but not to lipid defects. http://science.sciencemag.org/content/351/6274/737

These genetic changes were likely due to evolutionary pressure and various hypothesis such as the Grandmother Hypothesis, vitamin D and skin melanin, diet, climate changes, and exercise, are ably discussed by Raichlen and Alexander (2013) "Exercise, APOE genotype, and the evolution of the human lifespan," doi: 10.1016/j.tins.2014.03.001 Trends Neurosci. 2014 May; 37(5): 247–255. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4066890/
The discussion should not surprise those here in apoe4.info but perhaps give us some more scientific hints at lifestyle changes. As usual, 23andMe doesn't help much.

[Bernie]

I’m not sure, but I think they would already know whether Neanderthals had ApoE4. What I’ve read about is that certain of our HLA genes come from Neanderthals. I figure if Neanderthals were notably ApoE4 we’d already have heard it, but not sure. I think you must be right about that though?

Do you know which HLA genes have a Neanderthal heritage?

[circular]

Do you know which HLA genes have a Neanderthal heritage?

Here's the press release and here's the paper:
A novel family of human lymphocyte antigen class II receptors may have its origin in archaic human species

I can't make heads or tails of the little bit that I've read, other than it has to do with identifying pathogens. Checking the genes reported in the Insitome app I mentioned above, if they're referring to the same thing or even part of it, I have these specifics to add:

Interpreting Immune Signals (STAT2, Neanderthal is better but only found in 5% of people in non-African populations ... 'not having the Neanderthal variant, however, is not detrimental -- just different and largely based on geographical location'.) *

Pathogen Recognition (TLR1-TLR6-TLR10 [edit: adding 'Haplotype IV' and 'Haplotype III'] cluster, Neanderthal is better, and 'this improvement allows its carriers to better recognize pathogens, or biological dangers like bacteria and viruses, in their Northern Hemisphere environments. This modification to the TLR gene is widespread within non-African populations across the globe'.) *

Viral Immune Response (OAS [edit: adding DTX1, OAS1, OAS2, OAS3] genes, Neanderthal is better, but Insitome doesn't give frequency data here) *

It may be that more were discovered after this paper, or are these all somehow part of what the paper describes?

If someone else has time to read and summarize this here I'd appreciate it.

It's interesting to consider that even for anyone who inherited the Neanderthal versions of these genes, presumably they only confer added protection in the Euroasian environmenet. Once Europeans entered the new world, they would have encountered a host of foreign pathogens, while we also read about First Nation people dying of European illness they have never encountered. This may somehow dovetail with what Dr. Gundry is saying about how at least European settlers in the New World are not adapted to the lectins here that he indicates can jam the immune system.

I recall reading about paper years ago, before this Neanderthal talk or ever having through of apoe4, that said that people are unconsciously attracted to others with a complementary immune system; ie, couples will usually have different immune strengths and weaknesses so that the offspring won't be too lopsided. This trait may go all the way back and help explain why humans and Neanderthals interbred.

[Bernie]

Thanks for the links, I'll definitely be reading the paper! I'm fascinated by our evolved genome and how better understanding of it may provide insights on how we can better match our diet/lifestyle to it.

[Anna]

This is all quite fascinating -- and confusing! I think I need a summary in plain English.

I did some digging and couldn't find any evidence that Neanderthal DNA is over-represented in APOE4 carriers. If there is a connection, it could simply be Northern European ancestry.

But while on the topic of Neanderthal DNA, this 2017 study, The Contribution of Neanderthals to Phenotypic Variation in Modern Humans, is interesting:
https://www.cell.com/ajhg/fulltext/S0002-9297(17)30379-8
The researchers used a particularly large data bank to draw connections between Neanderthal ancestry and assorted traits. There was no mention of APOE or Alzheimer's. Some of the findings . . . Neanderthals don't carry variants associated with red hair in modern humans. There was an association with increased sun sensitivity and poor tanning. But the biggest finding was that "there are four phenotypes, all behavioral, to which Neanderthal alleles contribute more phenotypic variation than non-archaic alleles: chronotype, loneliness or isolation, frequency of unenthusiasm or disinterest in the last 2 weeks, and smoking status. Of these, the significant association between a Neanderthal variant in ASB1 and preference for evening activity also shows a correlation between the Neanderthal allele frequency and latitude, suggesting a link to differences in sunlight exposure for this phenotype." By "smoking status," they mean more likely to smoke. They conclude, "Skin and hair color, circadian rhythms, and mood are all influenced by light exposure. We speculate that their identification in our analysis suggests that sun exposure might have shaped Neanderthal phenotypes and that gene flow into modern humans continues to contribute to variation in these traits today."

[mike]

The only data I could find online about Neanderthal ApoE4 is in the paper by McIntosh et al. (2012) "The Apolipoprotein E (APOE) Gene Appears Functionally Monomorphic in Chimpanzees (Pan troglodytes)" PLoS One. 2012; 7(10): e47760.
doi: 10.1371/journal.pone.0047760 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3480407/ where alleles for rs429358 and rs7412 are "unknown." However, Denisovans according to this study were E4/E4, as were all humans (uniquely--chimps are not polygenic) until 300,000 to 200,000 years ago, when E3 and E2 arose. Currently earliest fossils of Neanderthals (derived from Homo erectus) in Europe are dated at 430,000 years ago, and thereafter Neanderthals expanded into Southwest and Central Asia, until they went extinct some 40,000 years ago.

Thanks for the search Verax! I've been busy with my son's wedding, but did read through them. They mention Denisovans ApoE status, but not Neanderthal...wonder why? So, my assumption is still that all early man was E4/E4, which makes sense since it is the earliest allele. Makes sense other primates are also E4/E4 then. They talk about E3 as being the Meat Allele, but that doesn't make sense, since there is now evidence that man had control of fire much earlier than previously thought:

https://www.history.com/news/human-ance ... an-thought

"The oldest unequivocal evidence, found at Israel’s Qesem Cave, dates back 300,000 to 400,000 years, associating the earliest control of fire with Homo sapiens and Neanderthals. Now, however, an international team of archaeologists has unearthed what appear to be traces of campfires that flickered 1 million years ago. Consisting of charred animal bones and ashed plant remains, the evidence hails from South Africa’s Wonderwerk Cave, a site of human and early hominin habitation for 2 million years."

So man had access to cooked meat much earlier than when the E3 allele showed up 220,000 years ago. What changed? I believe man first started cooking tubers, and I believe we should be calling the E3 allele the Carbohydrate Allele instead of the Meat Allele.