MUST READ for 3/4 carriers!

Insights and discussion from the cutting edge with reference to journal articles and other research papers.
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Julie G
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Re: MUST READ for 3/4 carriers!

Postby Julie G » Sat Feb 04, 2017 9:13 am

Julie I'd be worried about trying to raise output of apoe in 4/4 through higher cholesterol because if the apoe molecule produced isn't shaped right maybe raising its levels could cause issues?

Yep, that's what Mahley hypothesizes; hence the small structure corrector...BUT Rasmussen's work overrides that concern.

Plasma levels of apolipoprotein E and risk of dementia in the general population.
https://www.ncbi.nlm.nih.gov/pubmed/25469919
Abstract
OBJECTIVE:
The apolipoprotein E (APOE) ε4 allele is a major genetic risk factor for Alzheimer disease and dementia. However, it remains unclear whether plasma levels of apoE confer additional risk. We tested this hypothesis.
METHODS:
Using 75,708 participants from the general population, we tested whether low plasma levels of apoE at study enrollment were associated with increased risk of future Alzheimer disease and all dementia, and whether this association was independent of ε2/ε3/ε4 APOE genotype.
RESULTS:
Multifactorially adjusted hazard ratios (HRs) for Alzheimer disease and all dementia increased from the highest to the lowest apoE tertile (p for trends < 1 × 10(-6) ). Multifactorially adjusted HRs for lowest versus highest tertile were 2.68 (95% confidence interval [CI] = 2.04-3.52) and 1.80 (95% CI = 1.52-2.13) for Alzheimer disease and all dementia, respectively. After further adjustment for ε2/ε3/ε4 APOE genotype, plasma apoE tertiles remained associated with Alzheimer disease (p for trend = 0.007) and all dementia (p for trend = 0.04). Plasma apoE tertiles did not interact with ε2/ε3/ε4 APOE genotype on risk of Alzheimer disease (p = 0.53) or all dementia (p = 0.79). In a subanalysis, the -219G>T GT promoter genotype, associated with low plasma apoE levels, remained significantly associated with increased risk of Alzheimer disease after adjustment for ε2/ε3/ε4 APOE genotype (HR = 1.56, 95% CI = 1.05-2.30).
INTERPRETATION:
Low plasma levels of apoE are associated with increased risk of future Alzheimer disease and all dementia in the general population, independent of ε2/ε3/ε4 APOE genotype. This is clinically relevant, because no plasma biomarkers are currently implemented. Hence, plasma levels of apoE may be a new, easily accessible preclinical biomarker.

That being said, there are still cautions that need to be observed with raising LDL-C and hence TC. I still think all of our typical caveats apply with regard to LDL-P, Apo-B, sdLDL, oxLDL, Lp(a), glycemic markers, and other inflammatory markers. No one should take his as a free ticket to raise LDL-C sky high and throw all caution to the wind. That being said, It'll be interesting to learn the traits/diets of the 2 outliers in Reiman's current paper.

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Re: MUST READ for 3/4 carriers!

Postby Fiver » Sun Feb 05, 2017 7:42 pm

<deleted post so I can reread a study I mentioned>
Last edited by Fiver on Sun Feb 05, 2017 8:27 pm, edited 1 time in total.
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Re: MUST READ for 3/4 carriers!

Postby Nick » Mon Feb 06, 2017 9:33 am

The most important line in the report may be "Identification of APOE ε4 phenotypical characteristics in humans should promote experimental hypothesis-driven research linking pathological cell and molecular processes to APOE ε4. " ... or said simply "more research is warranted"

Some comments in this thread raise the question of self bio-hacking to increase cholesterol in hopes of improving AD progression or condition. This might be a bit of "reductionist" thinking and may miss the bigger picture. For example, if you subscribe to Preston Estep's view (based on his analysis of long mindspan individuals) that iron is the culprit (or a substantial culprit amongst others) in AD, then simply increasing cholesterol and triglycerides may be mal-advised:
- Raising cholesterol and triglycerides via non iron rich or non iron fortified foods may be beneficial
- Raising cholesterol and triglycerides via iron rich or iron fortified foods may not be beneficial
- Or maybe leaving cholesterol out of the discussion, letting it float as it so desires and focusing on iron reduction may be beneficial.

Also, I read a report somewhere (Posted here: viewtopic.php?f=16&t=2920) that the APOE ε4 may confer health benefits and is a human species promoting/enhancing characteristic. These benefits appear to be strongest at young and very young ages. Once again, bio-hacking oneself or others may, or may not, be beneficial.

I'm not proposing or discouraging any of the above mentioned bio-hacks. I'm not against bio-hacking oneself. But the human model is soooo complicated and the model is not well defined. How does one know if the actions trying to reduce AD don't result in you dying prematurely from cancer? "Oh want a tangled web".

The trouble is that we don't yet know. Maybe Estep's results are too much Reductionist Thinking. Or not. Or maybe something else is at play here. BTW ...my post on General Systems Thinking applies here. viewtopic.php?f=33&t=2919

I am reading a book on genetic genealogy (which started me down this path of discovery). It makes an interesting suggestion that the best and only advice you can get from understanding your genome is to "exercise more and eat healthy". Whatever that means.

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Re: MUST READ for 3/4 carriers!

Postby Julie G » Mon Feb 06, 2017 3:55 pm

You make some good points Nick. As E4 carriers we're forced to live with many uncertainties; hence the creation of this website. The choice to put epigenetics into practice based upon what now know is a personal one... and the only plan of action currently having a positive impact on Alzheimer's prevention and even reversal in the early stages. The strategies our organization endorses are those outlined in our primer. Outside of that, we discuss emerging research in an effort to glean possible strategic applications. Unfortunately, many of us at very high risk don't have the luxury of waiting until everything is sorted out before we act. It's very clear that a one-size-fits-all blanket protocol will never work for all E4 carriers. We encourage our members to partner with their physicians and become citizen scientists in an effort to glean possible strategies that may benefit them based upon their personal experience, family history, genetics, etc.

I suppose that your concern about reductionist thinking could apply if someone were to pick a solitary strategy based upon this paper. I warmly invite you to poke around the site in an effort to gain a broader picture of the multiple strategies that our members are employing. Just because this thread touched upon the notion that higher LDL-C is correlated with higher peripheral APOE (which has been found to be neuroprotective) doesn't mean that this is a singular strategy that anyone is advocating or utilizing without the caveats outlined in the posts above. Further, I can't find any posts recommending purposefully elevating triglycerides; nor does this paper find that correlation to be protective. Lastly, as you point out, by looking at every strategy through Preston Estep's lens one could also be accused of reductionist thinking. For now, I feel very comfortable employing a multifactorial approach to offset my very high risk of developing Alzheimer's that includes maintaining high LDL-C and low LDL-P. Current evidence reveals that this also puts me at a reduced risk of CVD. YMMV.

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Re: MUST READ for 3/4 carriers!

Postby Nick » Tue Feb 07, 2017 1:41 pm

I hope my post above is not interpreted as throwing water on the fire and enthusiasm of knowledge creation and acquisition. My apologies to all if so received. Also, don't let my reply derail the discussion but rather to build upon it.

Triglycerides were included due to their presence in the cholesterol creation pathway. As I recall, you will not have high cholesterol without high triglycerides and LDL molecules carry both triglycerides and cholesterol molecules.

My post above was a reaction to large number of variables associated with "cholesterol" and changing its level. There are sooo many factors involved that it is not clear how to project a result. Biohacking at the level discussed seemed to miss so many of the parameters.

The dirt is in the details and there is a lot of dirt to sift through here.

And now back to our regularly scheduled thread :D
Last edited by Nick on Tue Feb 07, 2017 2:29 pm, edited 1 time in total.

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Re: MUST READ for 3/4 carriers!

Postby circular » Tue Feb 07, 2017 1:53 pm

Nick it's good that now and then members chime in with the complexities. New people are coming along all the time, and it's easy for old-time members to get lost in rabbit holes. It's important that the perspective you have not be buried in the details. Then it's equally important that someone like Juliegee do such a good job articulating the balance we try to strike. There hasn't been a lot of posting in the last couple days in general, so I think it's safe to say your posts were taken in the spirit they were intended and people are just busy :)
ApoE 3/4 > Thanks in advance for any responses made to my posts.

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Re: MUST READ for 3/4 carriers!

Postby Julie G » Tue Feb 07, 2017 5:33 pm

Amen, Nick- so much dirt to sift through. I truly appreciate and share your cautions. That being said, as a newcomer it's very easy to focus in on one thread and not see the entirety of our process, be aware of our members' multifactorial approaches, and ultimate personal gamble regarding the adoption of new strategies.

As an aside, it's very possible to have low TGs with high LDL-C/low LDL-P (discordant in the right direction. Quite a bit of evidence suggests that this may even be optimal for our hearts and brains ;).

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Re: MUST READ for 3/4 carriers!

Postby circular » Tue Feb 07, 2017 6:17 pm

Nick, an n=1 for ya: Over the last year my total cholesterol went up from 145 to 161, LDL up from 79 to 83, (HDL up from 62 to 67), and TG down from 75 to 53. My LDL-P WAS 881 last year but I haven't updated that yet. So at least in my case the TG aren't in lockstep with TC and LDL.
ApoE 3/4 > Thanks in advance for any responses made to my posts.

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Re: MUST READ for 3/4 carriers!

Postby Nequals1Guy » Thu Feb 09, 2017 8:27 am

Juliegee wrote:
As an aside, it's very possible to have low TGs with high LDL-C/low LDL-P (discordant in the right direction. Quite a bit of evidence suggests that this may even be optimal for our hearts and brains ;).


I have very low TG's but high LDL-c, high Ldl-p. From a practical perspective here...based on the above discussion....are you saying that for 3/4's it may not be helping to drive the ldl-p down? I'm sorry but I'm a little confused. I thought the prevailing view is to try and drive the particle count down as low as possible.


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Julie G
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Re: MUST READ for 3/4 carriers!

Postby Julie G » Thu Feb 09, 2017 9:52 am

I have very low TG's but high LDL-c, high Ldl-p. From a practical perspective here...based on the above discussion....are you saying that for 3/4's it may not be helping to drive the ldl-p down? I'm sorry but I'm a little confused. I thought the prevailing view is to try and drive the particle count down as low as possible.

Read my post again. I recommended aiming for high LDL-C combined with low LDL-P. For those unfamiliar, LDL-C and LDL-P can often be discordant; where one is high, the other low. Evidence suggests that high LDL-C combined with low LDL-P is cardioprotective as you can see from the MESA graph below. Those with high LDL-C/low LDL-P were the least likely to suffer from a CVD incident. I worry when I see members focus exclusively on LDL-C as discordancy in the opposite direction (low LDL-C and high LDL-P) predisposes one to a CVD incident.
LDL-P-and-LDL-C-Discordance.jpg

That being said, Reiman et al didn't look at the LDL-P correlation in this paper. That was my speculation based on a larger body of evidence. In this paper, Reiman found higher LDL-C to correlate with higher peripheral APOE (primarily of the E3 isoform) to be neuroprotective.
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