New, with some questions

Newcomer introductions, personal anecdotes, caregiver issues, lab results, and n=1 experimentation.
t_rubi
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New, with some questions

Postby t_rubi » Wed Feb 20, 2019 11:47 pm

Hello,

I learned recently from genetic testing that I may be E4/E4, and I had a few questions. It's been a bit rough to process and there's so much conflicting information out there, so I was very happy to find this community - folks here seem to be very knowledgable and supportive, which is great.

First I wanted to confirm that I am interpreting my genetic info correctly. If I'm understanding everything right, the ApoE genotype is based on two SNPs, rs429358 and rs7412. My genetic data shows that I am C/C at rs7412, which is the E4 variant. I don't have sequence info for rs429358, but according to SNPedia (https://www.snpedia.com/index.php/Rs4420638) it looks like rs4420638 is a linked SNP that can be used to infer rs429358. I am G/G at rs4420638, which I believe is the variant associated with E4. So my question is, am I interpreting all this correctly? Also, it appears to be unresolved how good a predictor rs4420638 is of E4 status. Does anyone know anything about that? (edit: realized I swapped some SNPs, fixed now...)

My second question is how common the E4/E4 genotype is - I thought I read that it was very rare (like 3% of people) but when I tried to confirm that it was surprisingly hard to find information...

And finally I was curious if anyone knows of any resources out there for younger adults. I'm only 33, so probably on the earlier side of the spectrum. But I would definitely be interested in experimental trials, etc if they exist for younger adults. (Since, in my mind, prevention is really the only silver lining to having this knowledge at all.)

Thanks!
Last edited by t_rubi on Fri Feb 22, 2019 6:31 pm, edited 1 time in total.

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Re: New, with some questions

Postby Chameleon » Thu Feb 21, 2019 6:45 pm

Hi t_rubi,

Welcome to the APOE4 community! Glad you have joined us. I am not able to interpret the SNPs, but there are third party software programs that can. You didn't say whether this is from 23andMe or some other test. But for instance if it is from 23andMe, you can get the raw data file and run it through some other software, like Genetic Genie or Livewello. It can help you interpret it.

I would also recommend exploring the Primer because it contains a ton of information. And there is a Wiki page where you can search for specific items.

I think it is positive that you know at an early age and are taking the prevention approach.

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Re: New, with some questions

Postby Fiver » Fri Feb 22, 2019 9:13 am

Hi t_rubi. Welcome to the club. Data I have seen range from ~2-5% of people being 4/4. It depends on the population studied. But, in any case, it is a rather exclusive club. You might want to read up - the wiki here is a good place to start. There are some basic things we can do to reduce the risks. Many of these things would also reduce risks of cardiovascular disease and diabetes, among others. You also have lots of time on your side. While past progress has been disappointing there is every reason to think that the major medical advances coming along now - gene therapy/CRISPR, for example - will revolutionize medicine in the next couple of decades. (How's that for some Friday optimism??)
Four relatives with AD. Concerned, but hopeful. Introverted, but will talk about science.

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Re: New, with some questions

Postby t_rubi » Fri Feb 22, 2019 10:38 am

Wow, so it sounds like 4/4 is indeed quite rare. Since my first post I have read a bit more about expected progress in therapies, and you're right, it is very encouraging! Thanks for the responses.

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Re: New, with some questions

Postby slacker » Fri Feb 22, 2019 2:47 pm

Hi t;

Some of our members use Promethease or Dr Rhonda Patrick's data cruncher to interpret raw data from Ancestry or 23&me (if that is where you got your test results). There are many options at various price points.
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Re: New, with some questions

Postby NF52 » Fri Feb 22, 2019 6:21 pm

t_rubi wrote:Wow, so it sounds like 4/4 is indeed quite rare. Since my first post I have read a bit more about expected progress in therapies, and you're right, it is very encouraging! Thanks for the responses.
Hi t_rubi!

As someone twice your age with ApoE 4/4, I just want to reassure you that while rare-ish (geneticists don't view things as rare unless they are in far fewer than 1% of the population), ApoE 4/4 is also not something that means your future is written in stone. Here's a link to a snpedia page on the rs429358 allele you wondered about.https://www.snpedia.com/index.php/Rs429358
It does indicate that it is one of the markers for ApoE 4.

But at the same time, it's a great example of how crowd-sourced information isn't always either current or accurate. For example, the text of snpedia asserts that this raises your risk of Alzheimer's by 12x ! That's absurd for several reasons. Here's just a couple:
*The average risk of either Mild Cognitive Impairment (MCI) or dementia of any type for people with ApoE 3/3 (75% of people with European ancestry) is estimated at 10-15% by the age of 85. So 12 x 10 = 120% risk??
* The study that "found" that statistic was done in England based on "42 case-control series published before July 1996"! That means these were people diagnosed with Alzheimer's before MRI and other imaging tests were available, and who were referred to a particular study center for examination. Not a study that followed a population over time and determined who got Alzheimer's. More recent studies of "diagnosed" AD cases using post-mortem brain studies have estimated that 30% of those diagnosed with AD did NOT have the disease.
Note: Actual likely risk: A 2017 meta-analysis on far more recent population-based incidence, showed that people with ApoE 4/4 who are in my age range and older (60-75 years), have a 30-55% risk statistically of eitther MCI or AD by the age of 85.
APOE-related risk of mild cognitive impairment and dementia for prevention trials: An analysis of four cohortsThat's important, since we have a lot of "mileage" on our brains, so anyone younger than us has much more ability to influence their risk.

So first piece of advice: read everything on ApoE 4/4 "risk" with a dose of skepticism.

Second piece of advice: Take great comfort in the fact that you are 33! Regardless of the general impression that "no progress has been made" in studying Alzheimer's in the last 20 years, that's simply not true. It's now known to be a highly complex disease, with multiple layers of pathology, and multiple lifestyle factors that can move the needle on risk. (The Primer is a great source for more on those.)

Alzheimer's research is happening as every great university and research center in the world--not just in pharmaceutical companies. I got to meet in December with lots of Ph.D's a few years older than you who are working on cutting edge research funded by government grants. One of them, who had multiple relatives with Alzheimer's told me that he was confident that by the time people his age needed it (say by the age of 50) it would be possible to give personalized recommendations to people based on a sophisticated understanding of who was at risk from tau, who from amyloid, who from inflammation, who from insulin resistance, who from vascular issues, etc. etc. By identifying people with high risk early, they would be able to be monitored and given appropriate recommendations and interventions long before their brains were damaged.

And as long as there are people twice your age who have ApoE 4/4 who are doing fine, you should feel confident that you will also--with some good decisions that you are already making!
4/4 and still an optimist!

t_rubi
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Re: New, with some questions

Postby t_rubi » Fri Feb 22, 2019 6:41 pm

Thanks for the detailed info! I did see since my last post that the "12X risk" study suffered from some serious flaws, and the newer estimates of likelihood and age of onset are much more heartening. I'm already feeling much more optimistic about everything. I am still struggling with whether to share this information with family... this thread has been very helpful, so I may make another post about that to see if I can get some input!


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