My Story and Questions

Newcomer introductions, personal anecdotes, caregiver issues, lab results, and n=1 experimentation.
WanderingMuggle
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My Story and Questions

Post by WanderingMuggle »

Hello all,

I have been lurking for a while now but thought it was time to post my story. I am a 66 year old male who has, per 23andMe/Promethease, one copy of the Apoe4 allele. Actually, this result was somewhat of a relief since my mother and two of her siblings were diagnosed with AD at about the same age as I am now. I have always assumed that all three of them were probably 4/4 for Apoe.

Though I had not heard of Dr. Bredesen until about a year ago, I had a severe problem with acid re-flux in my mid-fifties and I adopted a variation of the Bredesen diet at that time. My diet, for years, has largely been gluten fee, grain free, dairy free, red meat free and processed food free. Luckily, only when I go off diet do I experience episodes of brain fog. I do, now, follow parts of the rest of the Bredesen protocol. Most importantly, I take methy B vitamins to compensate for the fact that I have two copies of the MTFHR C677T mutation . Also,I have had some measure of success in reducing stress, increasing Vitamin D intake, increasing quality of sleep and implementing the 3/12 fasting protocol. I really haven't taken on any of the other steps in the Bredesen protocol however.

My biggest concern right now is I have a double mutation at rs669 which, per the SNP description, increases my risk for AD by 3.8X. This is actually higher than the reported risk for having a single copy of Apoe4 (which is a 2X risk). Furthermore, a double mutation at rs2333227 apparently works in synergy with a double mutation at rs669 to increase the AD risk by an astounding 25X over baseline. Unfortunately, I initially could not determine if I carried the rs2333227 mutation because 23andMe/Promethease does not report on this SNP. There is, apparently, another SNP, however, that is in "perfect linkage disequilibrium" with rs2333227. 23andMe does report on this SNP and I determined that I probably carry one copy of a mutated allele in the linked SNP. Consequently my risk factor related to this SNP combination is somewhere between 3.8X and 25X. I am curious if anyone here has studied these two SNPs and has any insights. Perhaps these SNPs have simply not been studied enough yet for the reported risk factors to be very reliable.

Actually I am okay with all of this. I feel that everyone has elevated genetic risks somewhere in their profile, whether those risks be for heart disease, cancer, autoimmune disease, etc. I am thankful that genetic research has given me the opportunity to pinpoint my risk areas and take steps to reduce these risks.
NF52
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Re: My Story and Questions

Post by NF52 »

WanderingMuggle wrote:Furthermore, a double mutation at rs2333227 apparently works in synergy with a double mutation at rs669 to increase the AD risk by an astounding 25X over baseline. Unfortunately, I initially could not determine if I carried the rs2333227 mutation because 23andMe/Promethease does not report on this SNP. There is, apparently, another SNP, however, that is in "perfect linkage disequilibrium" with rs2333227. 23andMe does report on this SNP and I determined that I probably carry one copy of a mutated allele in the linked SNP. Consequently my risk factor related to this SNP combination is somewhere between 3.8X and 25X. I am curious if anyone here has studied these two SNPs and has any insights. Perhaps these SNPs have simply not been studied enough yet for the reported risk factors to be very reliable.
Welcome WanderingMuggle,

You have found a community of people who love tackling thorny issues with sometimes elusive answers (and Harry Potter fans)
Here's some possible good news:
The original 2004 study that suggested an increased risk was done with only 148 people, all of whom came from a referral center for AD in Calabria, Italy. We don't know if those 148 people happen to be all DNA relatives or otherwise had common environmental or lifestyle risk factors. (Since my mother was one of 11 children of a father who himself was one of seven, I am sure I have at least 148 second to fifth cousins living within 50 miles of where they all started.) Finding that people who have Alzheimer's carry a particular SNP is much less conclusive proof of its risk association than a population-wide genomic analysis.

One of the other sources cited in SNPedia for the association between the A2M gene and a possible elevated risk of Alzheimer's is a 2014 meta-analysis of 39 studies with over 6000 cases of the rs669 risk allele. The abstract below found that even when looking at people with ApoE 4, there was "insufficient evidence" of any increased risk.
Influence of Alpha-2-Macroglobulin 5 bp I/D and Ile1000Val polymorphisms on the susceptibility of Alzheimer's disease: a systematic review and meta-analysis of 52 studies.
Abstract
Accumulating studies have evaluated the association of Alpha-2-Macroglobulin gene (A2M) 5 bp insertion/deletion (5 bp I/D, rs3832852) and Ile1000Val (rs669) polymorphisms with Alzheimer's disease (AD) risk, but the results remain inconclusive. To investigate whether these two polymorphisms facilitate the susceptibility to AD, we conducted a comprehensive systematic review and meta-analysis. Databases of PubMed, Embase, Web of Science, Medline, CNKI, and Google Scholar were searched to get the genetic association studies. All statistical analyses were conducted with Review Manager 5.2 and STATA11.0. Fifty-two articles were included in the final meta-analysis. We performed meta-analysis of 39 studies involving 8,267 cases and 7,932 controls for the 5 bp I/D polymorphism and 27 studies involving 6,585 cases and 6,637 controls for the Ile/Val polymorphism. Overall results did not show significant association between these two polymorphisms and AD risk in dominant, recessive, and multiplicative genetic models. On the stratification analyses by ethnicity and APOE ε4 status with genotypes of polymorphism sites, similar negative associations were found. The meta-analysis suggests that there is no enough evidence for associations of A2M gene polymorphisms (5 bp I/D, Ile1000Val) with AD risk at present, even after stratification by ethnicity and APOE ε4 with genotypes of polymorphism sites. However, due to the heterogeneity in the meta-analysis, the results should be interpreted with caution.
[Emphasis added.]

It sounds like you are doing great at 66 (which is my age, and I feel pretty mentally alert also). Your decisions to heal your acid reflux have likely made a great improvement in your gut microbiome and allowed you to feel healthy enough to reduce stress, sleep better and enjoy life.

We enjoy "lurkers" and are also happy when they share their own stories, add to our knowledge--and cause us to check out interesting stuff! If you haven't seen it, the Primer, the Glossary for the Primer both by a physician member who is ApoE 4/4, are full of great ideas on how to wade into the deep end in ways that make sense to you as an individual.

And if you happen to be a dad, in addition to a SNP sleuth, Happy Father's Day!
4/4 and still an optimist!
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KellyS
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Re: My Story and Questions

Post by KellyS »

Good afternoon, WanderingMuggle!

First of all, I love the name. Second, of all, welcome to our forum!
I am admiring at how pro-active you are, I think that one of the hardest challenges for many people is changing their dietary habits, but it sounds as if you have hit the ground running. Also, diving into Dr. Breeden's protocol PLUS the whole SNP/methylation topic is no easy feat. I continue to be in awe at how much the human genome project has blossomed, and what we are continually learning about genetics, not only as they relate to our ancestry, but to our health. The one thing that we always like to stress in our forum is that our genetics don't determine our destiny - but from the sounds of it, I am feeling that you already know this.

I know that you said you have been "lurking" for a while, so you may already know of the Primer that is available on the forum. It is full of so much information, and it can be found here: viewtopic.php?f=33&t=1418
If there is a topic you would like to read about, simply click on the magnifying glass icon in the top right corner of the screen, and there is also a "Wiki" page as well, just above the icon.

Know that there is nothing but love and support here, and a place where you're sure to get an answer to whatever questions you may have. Take care.
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WanderingMuggle
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Re: My Story and Questions

Post by WanderingMuggle »

Thank you KellyS and NF52 for your welcome and for your insights. I guess I should be more skeptical of some of the "findings" posted in the SNPedia that don't yet appear to be backed by solid data. My first clue should have been that a high "odds ratio" or risk should not be combined with a relatively low "magnitude", as assigned by Promethease, unless the data is very thin. I will continue to lurk and maybe post again if I feel I have something to add.
ann9787
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Re: My Story and Questions

Post by ann9787 »

I too have just found out that I have the rs669 (G,G0 after running my 23andme raw data through codegen.eu. I am confused about something and was hoping to get some clarification from someone with a better understanding than I have. This is what is listed on the codegen.eu site: "On its own, rs669 was not seen to reproducibly and independently increase risk for Alzheimer's disease in several studies of ~200 Italian patients. However, the T-C-A haplotype of rs12316150-rs1050283-rs669 was associated with both early- and late-onset Alzheimer's disease. The majority of the disease risk from this haplotype was based on rs1050283.[PMID 18191876]".

Two things are confusing me the most. The first is the haplotypes listed do not show up in my raw data. The second is the last sentence "The majority of the disease risk from this haplotype was based on rs1050283. This again, does not appear in my raw data.

If the majority of the disease risk is for a haplotype I do not have, how could I be at such a high risk? According the codegen.eu, I have a 3.8x or higher risk of AD. Am I missing something? Two days ago I didn't even know what a haplotype was, perhaps still don't. :? Thanks in advance.
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floramaria
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Re: My Story and Questions

Post by floramaria »

ann9787 wrote:I too have just found out that I have the rs669 (G,G0 after running my 23andme raw data through codegen.eu. I am confused about something and was hoping to get some clarification from someone with a better understanding than I have. This is what is listed on the codegen.eu site: "On its own, rs669 was not seen to reproducibly and independently increase risk for Alzheimer's disease in several studies of ~200 Italian patients. However, the T-C-A haplotype of rs12316150-rs1050283-rs669 was associated with both early- and late-onset Alzheimer's disease. The majority of the disease risk from this haplotype was based on rs1050283.[PMID 18191876]".

Two things are confusing me the most. The first is the haplotypes listed do not show up in my raw data. The second is the last sentence "The majority of the disease risk from this haplotype was based on rs1050283. This again, does not appear in my raw data.

If the majority of the disease risk is for a haplotype I do not have, how could I be at such a high risk? According the codegen.eu, I have a 3.8x or higher risk of AD. Am I missing something? Two days ago I didn't even know what a haplotype was, perhaps still don't. :? Thanks in advance.
Hi ann9787,

Welcome! I answered your question about Promethease and ApoE genes in another thread before I saw this post of yours. Since my knowledge of genetics is limited, I confess I am just as confused by what you wrote above as you are. I am not familiar with the codegen.eu site. Someone here who has a better understanding of the different genetic variants you mention will be able to help you with this more than I can. Meanwhile, I'd like to welcome you here where you will find many other inquiring minds. It seems like you are taking a deep dive into your genetics, and I wonder what is prompting you to do that. If you care to share more of your personal story and what brings you to the website, Our Stories
is a good place to introduce yourself.
As I did in the other post, I strongly suggest that you have a look at the Primer. It is a tremendous resource providing a thorough overview of the ApoE4 genetic allele. It is written by a physician member and is an excellent place to begin.
We have a Search function that might also be helpful to you. Perhaps you could enter the individual haplotypes and see what other members of the community have posted previously. To access the Search function, click the magnifying glass to the left of your user name.
Very best wishes to you.
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IFM/ Bredesen Training in Reversing Cognitive Decline (March 2017)
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Re: My Story and Questions !BUMP

Post by cloudgirl7 »

I have gotten this exact same gene hot when putting my raw data in that same sight, can someone help clarify this? Or explain it in better terms
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Re: My Story and Questions !BUMP

Post by NF52 »

cloudgirl7 wrote: Fri Jun 02, 2023 3:53 pm I have gotten this exact same gene hot when putting my raw data in that same sight, can someone help clarify this? Or explain it in better terms
Hi cloud girl7!

I'm guessing that the gene variant you're referring to is rs669, but if it is something else from your Promethease report, let us know. Everyone has two copies of rs669, one from each parent. You and I may both have one rs669C and one rs669T.

What scientists don’t yet clearly know is: Does rs 699 C/T increase the risk of Alzheimer's, or possibly Parkinson's disease, in ApoE 4 carriers?

This is one gene I don't worry about, until I see a lot more data on how it might affect those of us with ApoE 4. I'm 71 and have ApoE 4/4 and yet I am still well within the normal range cognitively and plan to stay that way for a long time.

Here's what I found from a 2022 research article that combined data from several studies of almost 900 people with Parkinson's disease (NOT Alzheimer's) and almost 1300 people without Parkinson's Disease (referred to as PD below). You can see that even when they went looking for an association with this gene and a disease that affects the brain, they found it only in people with other dominant (i.e. inherited Parkinson's) and even then mostly in people identified as Asian.
A total of 877 PD patients and 1296 controls from six studies were included for rs669 polymorphisms. The combined odds ratio (OR) indicated that rs669 polymorphisms were likely associated increased risk of PD only in dominant genetic models (OR = 1.41, CI = 1.03-1.92), especially in Asian subgroup (OR = 1.97, CI = 1.03-3.75).
Association between two α-2-macroglobulin gene polymorphisms and Parkinson's disease: a meta-analysis

And here's an excerpt from the conclusions in a 2014 article, specifically on ApoE 4 and risk of Alzheimer's with rs669 (also called A2M):
We performed meta-analysis of... 27 studies involving 6,585 cases and 6,637 controls for the Ile/Val [i.e rs669] polymorphism.... The meta-analysis suggests that there is not enough evidence for associations of A2M gene polymorphisms... with AD risk at present, even after stratification by ethnicity and APOE ε4 with genotypes of polymorphism sites.
My "translation": "Even after we looked at Alzheimer's disease risk specifically in people with ApoE4, we didn't even find it associated with a risk of Alzheimer's disease."

Hope that gives you some peace of mind!
Nancy
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Jane S
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Re: My Story and Questions !BUMP

Post by Jane S »

cloudgirl7 wrote: Fri Jun 02, 2023 3:53 pm I have gotten this exact same gene hot when putting my raw data in that same sight, can someone help clarify this? Or explain it in better terms
Hello cloudgirl7!

As a Support Team Intern, I'd like to welcome you to the forum. There's a wealth of information around here - in the Primer, the Wiki, and in the postings of other members, like NF52. Other members may chime in with their insights, too.

There is so much being learned and so much yet-to-be learned about all the genetic influences. I find it most helpful to focus overall on all the things I can control, like the strategies in the Primer. The Primer is a detailed and informative resource written by a practicing M.D. with ApoE4/4. It includes information about the biochemistry of the ApoE4 gene and offers a variety of research-based prevention strategies.

Some helpful tips to navigate the ApoE4.info site include the How-To Guide. It includes topics such as navigating the forum, private messaging, and searching. One great tip is using the quote (") button when replying to a post. Using the button will automatically alert the member of your response.

If you're interested in learning more about other members, you can check out Our Stories. And you can share more about your ApoE4 story there, too.

I'm so glad you joined and look forward to meeting up with you in other posts. Please feel free to reach out anytime.

Take care.

Jane
-- Jane --
(daughter, granddaughter, and niece of people who lived with Alzheimer's)
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Re: My Story and Questions

Post by cloudgirl7 »

Thank you Nancy and Jane! My father died from Parkinsons so im gonna do more research on this gene, but thank you so much for the info on that!
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