Confusion about genetic ApoE status (direct genotyping vs. predictive SNP)

[Afraid]

I did a consumer genetic test and worry about my ApoE status because I see a conflict between my ApoE alleles based on rs429358 and rs7412 with the predictive SNPs like rs4420638 and especially rs769449.
The minor alleles of these SNPs are commonly co-inherited with an ApoE4 allele and I am heterozygous for both, yet according to rs429358, I am ApoE3/3.

According to the paper linked below, there is only one rs769449 A ApoE3 haplotype with a frequency of just 0.27%, while all other rs769449 A are ApoE4 (20% of the population and close to all ApoE4 carriers)
Meaning that rs769449 A is 100 times more often inherited with an ApoE4 allele.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1978251/
If all my genotyped SNPs are correct, I am the rare Haplotype No 20 in this table.
https://www.ncbi.nlm.nih.gov/pmc/articl ... /table/T1/

So my question, what are the odds? Am I one of the lucky 1% rs769449 A ApoE3 carriers or am I one of the 20% ApoE4 carriers and my rs429358 TT is a false negative?

I never had been this insecure about my health and it is a heavy weight on my shoulders.
All thoughts about this and how I should go on are very welcome.
Best regards.

[Plumster]

Hi Afraid,

I can't say about your risks, but I did this test (described in the link + following discussion below) because I was also curious about my risk. It will likely calm you greatly to take it. Alternatively, perhaps others here can help you out.

viewtopic.php?f=16&t=3029

[NF52]

I did a consumer genetic test and worry about my ApoE status because I see a conflict between my ApoE alleles based on rs429358 and rs7412 with the predictive SNPs like rs4420638 and especially rs769449.
The minor alleles of these SNPs are commonly co-inherited with an ApoE4 allele and I am heterozygous for both, yet according to rs429358, I am ApoE3/3....
I never had been this insecure about my health and it is a heavy weight on my shoulders.
All thoughts about this and how I should go on are very welcome.
Best regards.

Welcome, Afraid,

It sounds like you picked a user name for yourself that best describes what you are feeling right now--or at least what you were feeling when you picked that name. Hopefully, we can help you feel less afraid, no matter what answers you get to your interesting questions.

So here's a question for you first: I put "bold" font on your statement that according to rs429358 you are ApoE 3/3. That Snp, if it came back as "T', would indicate that you have one ApoE 3 (assuming it was correct). But you would also have to look at the result of rs7412, which would be "C" if that is also ApoE 3, according to the handy chart on SNPedia: https://www.snpedia.com/index.php/APOE. Are those the results you received?

If so, then it seems you are in fact ApoE 3/3. As for the 2007 article you cited showing a miniscule chance of having a different SNP result on rs4420638 and especially rs769449 that is usually linked with ApoE 4, I would say that genome wide association studies have progressed exponentially in the last 12 years. In fact, when I do Google Scholar searches now, I usually restrict the time search to 2015 or later. Studies I have seen suggest that other SNPs can have a small, or sometimes not so small association with Alzheimer's and other diseases without being completely linked with ApoE 4. Some users use the service Promethease to get a report on all their SNPs. I've used it, and have to say the results were easily readable. https://www.snpedia.com/index.php/Promethease

One other possibility: you didn't say which consumer company did your test. If it was 23&me, they seem to have about a 99% accuracy rate, and have sometimes confirmed results when people ask them to check. If it was Ancestry, they seem to always return a result of ApoE 3/3, for reasons I don't understand. Here's a forum thread on that subject.APOE mismatch Ancestry vs 23andMe

I hope you'll be able to untangle this through either Promethease or using another testing service and will let us know the results.
And remember: Genes are not destiny!! Even someone like me, at age 66 with ApoE 4/4, probably has a better than even chance of getting to the age of 85 (which is about how long people in my family live) without having a diagnosis of Alzheimer's. And the corollary to that is that being ApoE 3/3 is no guarantee of not having Alzheimer's in late old age. We may not be able to control the final outcome of our lives, but we have lots of choices to make about how we journey through it. Check out Stavia's Primer for great ideas for anyone on living a healthy, purpose-filled, joyful life.

We're here for each other, "Afraid". Let us know how we can help calm your fears. Hugs.

[Afraid]

Thank you very much for welcoming me with such an awesome and in-detail reply.

So here's a question for you first: I put "bold" font on your statement that according to rs429358 you are ApoE 3/3. That Snp, if it came back as "T', would indicate that you have one ApoE 3 (assuming it was correct). But you would also have to look at the result of rs7412, which would be "C" if that is also ApoE 3, according to the handy chart on SNPedia: https://www.snpedia.com/index.php/APOE. Are those the results you received?

Yes, those are the results I received from LivingDNA and rs 7412 is indeed CC. They use an Illumina GSA beadchip, which is the same technology as the 23andme V5 chip, only a few custom SNPs are different. The whole file was analyzed with Promethease and I got quite a mixed bag for Alzheimer's related alleles, but nothing above a 3 magnitude. Only after I realized how many SNP's in the ApoE region I had the risk variant for, I started to dig deeper and questioning my results.

One other possibility: you didn't say which consumer company did your test. If it was 23&me, they seem to have about a 99% accuracy rate, and have sometimes confirmed results when people ask them to check. If it was Ancestry, they seem to always return a result of ApoE 3/3, for reasons I don't understand. Here's a forum thread on that subject.APOE mismatch Ancestry vs 23andMe

I hope you'll be able to untangle this through either Promethease or using another testing service and will let us know the results.

Concerning the accuracy rate, the Illumina GSA product fact sheet gives a call rate of 99% and a "reproducibility rate" of 99,9% average across all genotyped positions. Since some SNPs are more difficult to assay accurately than others, I am unsure what to believe in. Honestly, a 99% accuracy rate for rs429358 doesn't sound too good and makes me wonder about their FDA approval. This will leave a lot of customers in a false sense of security about their risk.

I have been trying to guesstimate my risk based on the haplotypes in the paper linked in the first post.
Based on rs769449 being GT, there is this one 0,27% frequency E3 haplotype and roughly 18% frequency E4 haplotypes.
If I am genotyped correctly, I would be in a 0,27% haplotype. The odds of just this are about as high as being wrongly genotyped.
Since this is neglecting the other positions not included into this haplotype, it might have been a futile attempt for a little hope.

Yesterday, I arranged a meeting with a genetic counselor. Hopefully I can get a medical-grade ApoE sequencing, but it will probably take at least six weeks until everything is done.
Of course I will get you updated about my ApoE status. Given the plethora of my variants in linkage disequilibrium with an E4 allele, there is very little optimism left and I better not expect that the next test will confirm my E3/3 status.
A few words about Alzheimer's in my family, there is luckily not too much to report. A great-granduncle on my mothers side is the only confirmed case I know about. Several great-aunts and a grandmother lived into their late 80s, two had non-Alzheimer's dementia in old age.

I can only thank again for the welcome and information you provided me with. It greatly helped mitigating my fear. Hopeful that the time until definitive results are in will not have me in the same anxiety since realizing that there is something not right.

Best wishes.

[slacker]

Hi Less-Afraid;
Here's a prior thread discussing conflicting ApoE4 results, and companies that seem to be more accurate. Hope it helps.

[dcox]

Thank you very much for welcoming me with such an awesome and in-detail reply.

I can only thank again for the welcome and information you provided me with. It greatly helped mitigating my fear. Hopeful that the time until definitive results are in will not have me in the same anxiety since realizing that there is something not right.

Best wishes.

Welcome Less-Afraid!
It looks like you have been given some great information and encouragement from Plumster, NF52 and Slacker.

I'm going to reiterate something NF52 said Genes are not destiny!! This is so true and there are many things we can do to mitigate the way our genes are expressed (epigenetics), even if we are not 100% positive which ones we have. Both the Bredesen and Gundry protocols, which many on the sight follow help not only for AD, dementia and cognitive decline but for overall health and wellbeing of pretty much anyone who wants to prevent these outcomes and many other chronic "dis-eases" no matter what genes they have. Please take heart genetics is only a piece of the puzzle, find your hope as you explore this sight and see how others are preventing, reversing and stopping AD in it's tracks.

I realize the information can be overwhelming and NF52 recommended starting with the Primer , it is amazing, giving you great information about ApoE4 and the journey to prevention, reversal and stopping AD, one of our of our most active members, Stavia, put it together she is a Dr. and E4/E4 herself, she truly put her heart into writing it. If you want to take a deeper dive into specific topics our Wiki Page is loaded with information. This page will help you to navigate the site more efficiently "How-To" Get the most out of the ApoE4.info website.

While you are waiting for your more definitive results, I encourage you to take note of the things that bring you joy so if anxiety and fear come knocking on your door you're ready and able to turn them around and find hope in doing something you love. You can also always reach out here with questions and concerns, everyone here is passionate about this journey and willing to offer support to you on yours.

I hope you will find all the hope and encouragement you need, just know you are never alone in this amazing community.

Find your joy and hope in each new day and each new discovery along your path,
Deb

[Afraid]

A great Thank You to everyone who contributed to this thread and the whole forum.
Personally, the worst thing is not knowing. rs429358 TT and rs7412 CC alone tell me I am in the average ApoE3/3 risk group, but it is so hard to believe when the other odds are terribly against me. Maybe this is overly pessimistic and a distrust in genotyping accuracy. At this point I feel like 99,99% having one E4.
And therefore have to admit that this is a psychological issue too. Nothing is lost yet. I read the protocols provided (thanks!). ApoE4 is a risk that might, might not impact my late life at all. It is not my destiny. But I just can't fully bear it for now. Being a noncarrier and following a healthy lifestyle advice would give me the feeling of improving my life. Being a carrier gives me the impression that every action in my life from now on must be gauged on the impact of my ApoE risk factor. Hence the choices to mitigate my Alzheimer's risk aren't an improvement, but just trying to catch up with the rest, risk wise. I know that a healthy lifestyle is always an improvement, something I enjoyed in the past and ApoE doesn't change it a bit. But I can't feel the joy anymore, just compulsion.
I'm terribly sorry if this insults any readers point of view about being in the risk group. Reading the forum gives an overall impression of optimism and perseverance. There is nothing better than sticking to this spirit.

If so, then it seems you are in fact ApoE 3/3. As for the 2007 article you cited showing a miniscule chance of having a different SNP result on rs4420638 and especially rs769449 that is usually linked with ApoE 4, I would say that genome wide association studies have progressed exponentially in the last 12 years.

It is truly a difficult topic, with many little factors having a more than expected influence on the outcome. Thanks for the advice, cross-referencing changed the picture a very little bit. The paper mentioned uses a mixed reference for Europeans and it seems that the linkage of ApoE SNPs is always tight, but rather heterogenous within the continent. They found rs769449 in a stronger linkage diseqilibrium than a 2018 paper with a mixed German reference population, which should be a better match for my genetic background.

No matter what the results of further genotyping will show, a promise, I will share it here.
Maybe we can learn more about genotyping false negative errors and how predictive the adjacent variants truly are.