Question about my risk

[LasVegasGirl01]

I am scared and stunned by my genetic results and am hoping to learn more about what I can do to delay the onset of Alzheimer's.

I received my results from 23andme and uploaded them to Promethease to receive more informative reports.

I am APOE4/APOE3
I also have snp rs1799724 CT which indicates that in the presence of APOE4 my risk for Alzheimer's is increased by 6.6X
I also have snp re2075650 GG which is associated with earlier onset of late onset Alzheimer's by 7 years. This is a rare allele with a frequency of 3.5%
I also have other deterimental Alzheimer's related snps which I will not list in this post

I am a 51 year old female and had an oophorectomy at age 45. I have taken estrogen, but not a very high dose. I had no idea that I had such a strong chance of getting Alzheimer's and was more concerned with cancer risk which is why I kept my estrogen dose low. This definitely works against me since oophorectomy and low estrogen is associated with increased Alzheimer's risk.

My mother died of breast cancer at age 71. She did not have any dementia.
My father is 74 years old and was diagnosed with Alzheimer's in the past year. He has quite a number of issues with his heart and other health conditions.

I am 5'6" and weigh 110lbs. I exercise 7 days a week. My overall cholesterol is 201 and my good cholesterol is 68. EDIT: I am a practicing CPA and attorney so I am definitely keeping my mind active with complicated problem solving and research skills.

I feel so doomed based on the results and am just looking for support and guidance on how to cope going forward. I have spent most of the weekend analyzing my results so all of this information is very new to me.

Thanks for listening.

AK

[slacker]

Welcome AK LasVegas Girl;

Many people are overwhelmed when they receive their genetic news. Luckily, there is much that we can do to reduce our risk of cognitive decline. A good place to start is our primer which you can find here:
viewtopic.php?f=33&t=1418

There are many threads throughout our site that discuss risk; we find that different studies quote different percentages so there is some uncertainty about risk percentages. I personally am not a snp expert so can not comment on these; however from my perspective, knowing that there are lifestyle changes I can make to reduce my risk is powerful.

Lastly, there is a very long thread about hormone replacement for women and I think a wiki within our site as well. I suggest slowly reading and digesting the primer first before going down the hormone path. If you can't find the thread or wiki on hormone replacement via our search function (when you are ready), let us know and one of the "veterans" will help you.

[Julie G]

Welcome LasVegas Girl! Sorry that you're feeling distressed. Many of us felt that way at first. I promise it gets better with time. Epigenetics are real. There are many strategies that you can begin applying today to reduce your risk. Our primer outlines the basics. Take your time absorbing it all and feel free to ask questions along the way.

You may have accidentally stumbled upon the best solution for you with regards to HRT. Women who have early oophorectomies without estrogen supplementation are at increased risk of AD. The fact that you are supplementing, albeit with a low dose, is likely protective. Have you ever had any of the BRCA testing to better tease out your risk?

[LasVegasGirl01]

Hi Juligee,

Yes, I did have the BRCA test. I tested negative so I feel comfortable taking the low does estrogen. I will review the information in the primer and continue to ask questions.

Thanks so much for your support!!

AK

[Harrison]

I also have snp rs1799724 CT which indicates that in the presence of APOE4 my risk for Alzheimer's is increased by 6.6X I also have snp re2075650 GG which is associated with earlier onset of late onset Alzheimer's by 7 years. This is a rare allele with a frequency of 3.5% I also have other deterimental Alzheimer's related snps which I will not list in this post

Hi AK,

Thanks for posting. I was not familiar with one of those SNPs, so I looked to see what was out there. In doing so, I discovered the dangers of what data ends up in Promethease / SNPedia.

For rs1799724, there are only two studies in PubMed related to Alzheimer's. One is from 2005 and the other is from 2012. The 2005 study presents big effects, but since there are no additional studies until 2012, it's quite possible nobody could replicate them. Then in 2012 a group in Italy looked at the effect of rs1799724 in combination with ApoE4 in older (80 years old plus). They found no additional effects if the subjects were already apoE4 positive. Looking only in 80 years old+ has its issues since the effect of ApoE4 will most likely have been observed in the last 60s or early 70s. However, I think the overall message is that only two studies on this SNP have been performed, one positive and one negative.

For the 2nd SNP, rs2075650, this general topic of TOMM40 has been very controversial in the Alzheimer's field. Some people think this has no additional impact beyond ApoE4. There are at least two studies in PubMed on this particular SNP saying this, as acknowledged on the SNPedia page.

It's quite overwhelming to get the promethease report and see lots of SNPs related to AD, but this is far from settled science. I think it does offer some insight into where someone might focus their energies. If the genetics point to potential issues with inflammatory pathways, you might want to work on lowering inflammation. If the genetics point you to potential problems with metabolism, you might want to work on glucose and insulin. You are on the right track by reviewing the primer and asking questions.

[LasVegasGirl01]

Harrison,

Thank you so much for the additional information --- this is just the help I am looking for.

I just received my 23andme results on Friday and spent the weekend beginning to investigate what this means. I am quite distraught and overreacting right now.

After I posted my message yesterday I was reviewing snp rs1799724 further and can see that the study I referred to was performed on only 500 people and was from 2005. I also could not find any further support for the position that I have a 6X increased rate of Alzheimer's. In fact, the PubMed study that I referenced ended the commentary with "Further investigation is warranted to assess the significance of these novel findings." So that should be enough for me to realize this is not set in stone.

I had a hysterectomy five years ago and elected to have my ovaries removed due to high incidence of breast cancer in my family. So I have done a lot of research regarding estrogen replacement and the risks associated with early menopause. So I understand studies vary in results and some studies are more reliable than others.

I have a few more questions if you have time to assist:

What type of genetics point to inflammation and what can be done to reduce inflammation? (Maybe I just need to reference the primer for the information)
Do you have any thoughts on Vitamin K2 (mk7) supplement?
Do you have any thoughts on Omega 3 EPA DHA supplement?
If the supplements are good to take, what dose is recommended?

I see a breast cancer risk specialist twice per year and she has recommended 3,000 units per day of Vitamin D3 and 500mg of Vitamin B12. I also take 2 Tums per day for Calcium and a Multi-Vitamin. I also take an 80mg aspirin each day.

I would like to fine tune my supplements and make sure I am taking the correct type and amount. Of course I understand there is no better way to get the nutrients than through diet adjustments but just wondering about the supplement route as well.

I am thin and exercise 7 days per week. My triglycerides are in the healthy range. My total cholesterol is 200 and my good cholesterol is 68. I am thinking about requesting some additional blood tests at my next physical and was wondering if you had any thoughts on what I should request.

I will continue reading the primer and try not to overreact to my Promethease data before I have fully investigated each snp. I do a lot of research for my job and my general nature is to yearn for a lot of information that I can read and analyze. My nature is also to worry -- a lot. So I know my initial post was out of fear and I need to slow down and read through the information more thoroughly.

Thanks so much for your support!!

AK

[Stavia]

Hi AK and welcome.
You are asking very good questions but unfortunately there are no black and white answers. Each of the questions will take you down a rabbit hole.
I recommrnd that you search our forum for each of the areas you are querying and spend about a month on getting to understand the nuances of each area. Then you can decide about what strategies you wish to follow. It doesn't have to be decided today.
I also recommend that you don't delve into any more snps until you understand more of the above. It's only going to upset you. And Harrison has explained how patchy and inconsistent the data actually is. I personally have stopped looking years ago.
You certainly aren't doomed. You are healthy right now and have time to understand and apply strategies.

[slacker]

AK -

The primer on our website referenced above gives basic information on supplements and lab testing, perhaps not in the detail that you are looking for, but it is a good place to start. Supplements in general don't have the most rigorous science behind them for cognition, and our members here have various positions on the need and wisdom of taking them. You can always do a website search on a particular supplement to see what has been discussed in the past.

Good luck, and happy hunting!

[SusanJ]

Hi LasVegasGirl. Lots to learn on this site. Really do study the primer and you'll be ready to research other areas with a better understanding. As others have said, the science is unsettled in so many areas.

Regarding:

What type of genetics point to inflammation and what can be done to reduce inflammation? (Maybe I just need to reference the primer for the information)

Have you tested your inflammatory markers? Are they high? Just because you have the genetics for it (I have several), doesn't automatically mean you will have inflammation if you get the other things right in our diet and lifestyle.

[Jack C]

I also recently found out that I have rs1799724C/T. And, I am an attorney (retired). Maybe rs1799724C/T increases the risk of going to law school.

I have done some research into this genetic marker. However, my understanding of DNA is superficial, the statistical formulas used in the studies are way over my head, I do not understand all of the jargon, and the even the parts of the studies ostensibly written in plain English rarely give up their meaning to me without a fight.

With that in mind, it looks like there are at least seven relevant studies and one meta-analysis of the first six of those studies. Three are of Northern Europeans, four of Southern Europeans
:
2001 Northern Ireland (lead author McCusker). http://www.thelancet.com/journals/lance ... 3/abstract

2005 Germany (Laws). PMID 15895461 This is the study that Promethease relied on. The link is just the abstract. I have read the full text, but cannot link it or print it.

2008 Australia (Gnjec). https://jneuroinflammation.biomedcentra ... -2094-5-36 The study was of Australians of Northern European descent (97% Causasians).

2002 Spain (Infante). No synergistic effect between -850 tumor necrosis factor-alpha promoter polymorphism and apolipoprotein E epsilon 4 allele in Alzheimer's disease. Neurosci Lett. 2002, 328: 71-73.
10.1016/S0304-3940(02)00453-6. I cannot find even the abstract of this.

2003 Italy (Terreni). https://doi.org/10.1016/S0304-3940(03)00434-8

2008 Italy (Tedde). http://europepmc.org/abstract/med/18834925

2009 Meta-analysis (Di Bona). http://www.sciencedirect.com/science/ar ... 7309000538 The link is just to an abstract. The full study should be attached.

2011 Italy (Albani). https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3312635/ Among its limitations, this study did not look specifically at AD, but at undifferentiated dementia.

As far as I can tell, only the German, 2008 Italian, and 2011 Italian studies were nominally of rs1799724. The other studies were of TNF-alpha-850, but they appear to be looking at the same thing. According to SNPedia, rs1799724 is near the TNF-alpha gene, “located at position -857 or -850 (varies).” The 2008 Italian study looked in the region of the “TNF-alpha gene” at the SNP “rs1799724 (-850C/T),” and the 2011 Italian study used the term “TNF-alpha-850C/T (rs1799724).” Most important, the 2009 meta-analysis included the German study with the -850 group. Also, AlzGene groups the studies together. http://www.alzgene.org/meta.asp?geneid=81&polyID=193

On the other hand, the Australian study said that the only previous study that had found a synergistic link between -850 and e4 was the Northern Ireland study, when the German study was out there. However, the German study states, “the polymorphism rs1799724 has also been linked to AD [in the Northern Ireland study],” and “our data does support the previous findings [of the Northern Ireland study] that the presence of the rs1799724-T allele increases the risk of AD in carriers of the APOE-e4.”

There are two issues. One is whether rs1799724 (-850)T increases the risk of AD regardless of APOE. The second is whether it has a synergistic risk-increasing effect with e4. I will try to summarize the findings of the meta-analysis.

Issue One:

With no consideration of APOE, the meta-analysis found that there was a “possible gene dosing effect with increase of copy numbers of the T allele leading to a higher OR.” Those with an -850T/T had a 60% increased risk of AD (OR 1.57). For T/T + C/T the OR was 1.21. And, for C/T alone, the OR was 1.15, “not achieving statistical significance.”

As someone who is predominantly of Northern European descent, I was concerned that the Northern European studies appeared to show a risk that the Southern European studies did not regarding C/T. The two highest ORs were Australian (1.80) and German (1.36). However, the lowest OR was Northern Irish (0.89). The later Italian study found only an insignificant association (OR 1.2).

Issue Two:

The meta-analysis also looked at whether there is a synergistic effect between APOE e4 and -850T. Northern and Southern European subgroups were analyzed separately. Data were not available from the underlying studies for each genotype, so the anlaysis was only for T/T + C/T combined.

The Southern studies showed no synergistic effect (cumulative OR 0.97). The later Italian study also showed nothing.

The Northern European studies had a cumulative OR of 1.95. (Northern Ireland 1.69; Germany 2.33; Australia 1.94.) So, there was a two-fold increased risk in e4 carriers with the -850T polymorphism. I think that means you take your risk for being e4 and double it.

The Northern Ireland study found that the AD risk for people with e4 but not the T polymorphism was 2.73. For those with both e4 and the polymorphism, the risk was 4.62. (If you multiply 2.73 x the OR (above) of 1.69, you get 4.62.)

The corresponding numbers in the German study are 2.92 for those with just e4 and 6.65 for those with both. (For some reason, multiplying 2.92 x the OR (above) of 2.33, you get 6.80 rather than 6.65.)

I first read the Australian study as not having found a synergistic effect. The meta-analysis, initially seems to confirm this: “Data for this [synergistic effect] analysis were available for all studies except the [Australian study], which however showed no interaction between the effect of TNF-alpha SNP and APOE e4.” Then, in apparent contradiction, the meta-analysis has the Australian study in a chart with data showing a synergistic effect, leading to the conclusion that “among Australians and Northern Europeans the risk of AD is about 2 fold higher in APOE e4 carriers with TT and CT genotypes ….”

Despite numerous re-readings of the study and the meta-analysis, I cannot figure out what I must be missing. The meta-analysis ascribes an OR of 1.94 to the study. And, an OR of 1.94 does appear in the study in a footnote to a chart, but I cannot tell what, if anything, it has to do with APOE.

In any event, if the gene-dosing effect seen in the first issue holds true here, the numbers for C/T alone should be somewhat lower than the above numbers for T/T + C/T . And, the meta-analysis noted that the “small or medium” size of the studies gave them “little statistical power.”

According to the meta-analysis, the difference between Northern and Southern European study results might be from genetic or environmental factors, or from the relatively low frequency of APOE e4 in Southern Europeans making those studies too small to detect the association.

Jack