Hormone Replacement Therapy E4 Women

Alzheimer's, cardiovascular, and other chronic diseases; biomarkers, lifestyle, supplements, drugs, and health care.
Silverlining
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Re: Hormone Replacement Therapy E4 Women

Postby Silverlining » Wed Nov 05, 2014 6:11 am

I give up! There is NO consensus on estrogen and APOE4 in the studies I've looked at for several months now. The paper Stavia provided is extremely comprehensive; they did a good job compiling information from numerous studies. There are two detailed tables with snps and risks that were interesting. The conclusion highlights that polymorphisms in the ESR1 gene correlate with AD, especially in females and yet they admit studies are inconclusive and contradictory. However, this paper from 2011 does not find any correlation between ESR1, ESR2 and genetic susceptibility for AD. (This study is mentioned on page 64 of the study Stavia (or Ski) just posted above.

Study of Estrogen Receptor-α and Receptor-β Gene Polymorphisms on Alzheimer's Disease
http://iospress.metapress.com/content/m4612ru130r7225u/

"Estrogen treatment can modulate the risk for developing dementia in women. Therefore, single nucleotide polymorphisms (SNPs) in the estrogen receptor genes may constitute genetic susceptibility factors to Alzheimer's disease (AD). Thus, we investigated the impact of the genetic variability of the estrogen receptor α 1 (ESR1) and estrogen receptor α 2 (ESR2) genes on late onset AD risk. We analyzed 39 SNPs in ESR1 and 5 SNPs in ESR2 in a French case-control study of sporadic AD (1007 cases/647 controls). Individuals carrying the minor allele of rs7450824 had a lower risk of AD than homozygous subjects for the major allele (age, gender, and APOE ε4 allele adjusted odds ratio = 0.71 [0.57–0.89], p = 0.003). However, this association did not resist Bonferroni correction for multiple testing (p-threshold < 0.001). Consistently, no significant association could be detected when considering age of onset. We also tested for possible interactions between the ESR SNPs and APOE status (ε4 allele) or gender but no significant interaction could be observed. Even after stratifying the sample on APOE status or gender, no significant association with AD risk could be detected. Finally, we searched for potential gene-gene interactions between ESR1 and ESR2 SNPs but no significant interaction could be detected. Our results reinforce the notion that SNPs in the ESR1 or ESR2 genes do not seem to play a major role in the genetic susceptibility of AD."

Hey, guess what, HRT for E4 women is about as clear as mud!

circular
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Re: Hormone Replacement Therapy E4 Women

Postby circular » Wed Nov 05, 2014 8:40 am

The abstract of the Stanford study begins:

"Apolipoprotein-ε4 (APOE-ε4) is a major genetic risk factor for cognitive decline, Alzheimer's disease (AD) and early mortality. An accelerated rate of biological aging could contribute to this increased risk."

Then it explores HRT and telemere shortening and finds the association between those. However, did it test cognitive decline to confirm that the telemere shortening necessarily caused cognitive decline while telomere length preservation prevented it? I suspect cognitive decline, perhaps moreso in E4s, isn't necessarily dependent on telomere shortening. We might keep our telomeres longer with HRT yet still be more susceptible to cognitive decline from the HRT? And yes, here the synthetic vs bioidentical becomes important and the research industry screws our chances at taking intelligent action once again by focusing on synthetics. We have to ascertain in what enviro/genetic circumstances keeping the telomeres longer also confers a cognitive benefit in E4s?
ApoE 3/4 > Thanks in advance for any responses made to my posts.

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Stavia
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Re: Hormone Replacement Therapy E4 Women

Postby Stavia » Wed Nov 05, 2014 9:21 am

Lilly I'll get it in an hour. 5am and I'm reading this under the duvet on my phone so as to not wake hubby.
But a sudden thought - the telomere thingy isn't necessarily a surrogate marker for AD. Then I see Circ said the same thing.
I'm still going to go on it for a while cos the menopause sleep deprivation/disturbance is awful. And that's gonna screw my chances majorly. Hopefully in 5 years more will be clear.

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Re: Hormone Replacement Therapy E4 Women

Postby circular » Wed Nov 05, 2014 10:30 am

How quickly we forget the "Bredesen principal"! :lol: How does HRT interact with E4 in the context of the rest of Bredesen's protocol, or some future refined improvement on it???
ApoE 3/4 > Thanks in advance for any responses made to my posts.

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Re: Hormone Replacement Therapy E4 Women

Postby Silverlining » Wed Nov 05, 2014 12:02 pm

A Levity Break:

Stavia, I burst out laughing at your response. I too was reading the study at 4:00 this morning UNDER THE COVERS so as not to wake my hubby!! How funny is that! I'm gonna smile all day thinking of our quirky little clique all around the world.

Alright, back to serious life altering business...

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Re: Hormone Replacement Therapy E4 Women

Postby circular » Wed Nov 05, 2014 12:29 pm

:lol: How's the coffee under there?
ApoE 3/4 > Thanks in advance for any responses made to my posts.

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Re: Hormone Replacement Therapy E4 Women

Postby Stavia » Wed Nov 05, 2014 1:08 pm

Lol!! Silver, the phone and my specs got all steamed up. I make a little tent over my head. How hilarious.
Circ - I don't like coffee. Only drink water. And the extremely occasional half a unit of whiskey or tequila ;)

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Re: Hormone Replacement Therapy E4 Women

Postby Stavia » Wed Nov 05, 2014 5:27 pm

LillyBritches wrote:Stavia - can you please pull this 2010 study? Very disturbing. :( :( :(

http://www.neurobiologyofaging.org/arti ... 97-4580(10)00440-9/abstract

Abstract
Associations between postmenopausal hormone therapy (HT) and cognitive decline may depend on apolipoprotein E (APOE) status or timing of initiation. We included 16,514 Nurses' Health Study participants aged 70–81 years who were followed since 1976 and completed up to 3 telephone cognitive assessments (2 years apart), between 1995 and 2006. The tests assessed general cognition (Telephone Interview of Cognitive Status; TICS), verbal memory, and category fluency. We used longitudinal analyses to estimate differences in cognitive decline across hormone groups. APOE genotype was available in 3697 participants. Compared with never users, past or current HT users showed modest but statistically significant worse rates of decline in the TICS: the multivariable-adjusted difference in annual rate of decline in the TICS among current estrogen only users versus never users was −0.04 (95% confidence interval, −0.07 to −0.004); for current estrogen + progestin users, the mean difference was −0.05 (95% confidence interval, −0.10 to −0.002). These differences were equivalent to those observed in women who are 1–2 years apart in age. We observed no protective associations with early timing of hormone initiation. We found suggestive interactions with APOE e4 status (e.g., on TICS, p interaction, 0.10), where the fastest rate of decline was observed among APOE e4 carriers who were current HT users. Regardless of timing of initiation, HT may be associated with worse rates of decline in general cognition, especially among those with an APOE e4 allele.


Then again, it states "may be." Good GOD. :(



here you go

you know, I'm going to take a leap of faith atm. I don't have enough biochemistry knowledge to really analyse all the minutae. I have come to the position of believing AD is multifactorial. Is has to be, the big picture of the data has to be interpreted that way as the only likely and logical explanation. Thus each factor cannot be viewed in isolation, it is the synergy of the many interventions that will be our protection. Its a tapestry, everything in context.

In addition, many trials lumped synthetic and bio-identical HRT together, muddying the waters.
I would NOT take synthetic HRT. Ever. EVER. I'm so so happy I had a few months on the pill age 20 and then never again.
But I am about to start bio-identical HRT. In combination with everything else I do. I am in the "window" age-wise and I feel the risk of me missing the window is greater than the risk of taking it for a few years until more data is out. Those of us who are still pre-menopausal have the luxury of time. Those of us in this window (which my functional doc said was until 65, dunno the evidence but there it is) have to make a decision. And IMO not taking HRT is a decision, as well as taking it is a decision. Here inaction IS a decision.
Sometimes everything is grey, and you have to make a choice.
In keeping with my "middle road" philosophy, I feel bio-identical HRT stands in the middle between the two outliers, the greater risks of no HRT and synthetic HRT.

Moderator note - I deleted the attached paper (DOI: 10.1016/j.neurobiolaging.2010.10.007) because our copyright infringement policy prohibits it. Members in jurisdictions for which access to Sci-Hub is legal may want to search for the paper there.

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Re: Hormone Replacement Therapy E4 Women

Postby Julie G » Wed Nov 05, 2014 6:23 pm

Secret undercover scientists; I can relate :geek:

I followed up on the Bredesen connection and hit the same brick wall that this paper did :? In his recent paper, Dr. Bredesen cites these 2 papers as references for his recommendation for maintaining hormone balance. The first we've seen before; discussing the synergy of combining strategies:

Next generation therapeutics for Alzheimer's disease.
http://onlinelibrary.wiley.com/doi/10.1 ... 02307/full

The second comes to the same disappointing conclusion that this current paper does. I will send him an email asking him if he STILL recommends HRT for E4s and share his response with the group.

Estrogen use, APOE, and cognitive decline
http://www.neurology.org/content/54/10/1949

Results: A total of 297 (11%) women were current estrogen users and 336 (12%) were past estrogen users. Over the 6-year average follow-up, baseline current users declined 1.5 points on the 3MS whereas never users declined 2.7 points (p = 0.023). Compared with ε4-negative women, ε4-positive women had a greater adjusted hazard ratio of cognitive impairment (3MS < 80), hazard risk [HR] = 1.47; 95% CI, 1.13 to 1.90. There was an interaction between estrogen use and ε4 presence (p = 0.037). Among ε4-negative women, current estrogen use reduced the risk of adjusted cognitive impairment compared with never users by almost half (HR = 0.59; 95% CI, 0.36 to 0.99), whereas, it did not reduce the risk among ε4-positive women (current use, HR = 1.33; 95% CI, 0.74 to 2.42). Compared with never use, current estrogen use was associated with less internal and common carotid wall thickening in ε4-negative women but not in ε4-positive women (p for interaction < 0.05 for both). Differences remained after adjusting for age, education, race, and stroke.

Conclusions: Estrogen use was associated with less cognitive decline among ε4-negative women but not ε4-positive women. Potential mechanisms, including carotid atherosclerosis, by which ε4 may interact with estrogen and cognition warrant further investigation.


Sigh. The evidence IS all over the place :shock: I keep coming back to mechanism. ApoE4 carriers exhibit reduced cerebral glucose in the same regions of their brains as AD patients starting as early as our 20s and 30s. What does estrogen DO for the brain? It regulates glucose transport to the brain. We already have reduced cerebral glucose. We hit menopause and experience reduced estrogen. Our brains experience even greater glucose deficiency. Estrogen also acts as a metabolic regulator. Metabolic derangement is strongly associated with AD.

Estrogen: A master regulator of bioenergetic systems in the brain and body
http://www.sciencedirect.com/science/ar ... 2213000435

Abstract
Estrogen is a fundamental regulator of the metabolic system of the female brain and body. Within the brain, estrogen regulates glucose transport, aerobic glycolysis, and mitochondrial function to generate ATP. In the body, estrogen protects against adiposity, insulin resistance, and type II diabetes, and regulates energy intake and expenditure. During menopause, decline in circulating estrogen is coincident with decline in brain bioenergetics and shift towards a metabolically compromised phenotype. Compensatory bioenergetic adaptations, or lack thereof, to estrogen loss could determine risk of late-onset Alzheimer’s disease. Estrogen coordinates brain and body metabolism, such that peripheral metabolic state can indicate bioenergetic status of the brain. By generating biomarker profiles that encompass peripheral metabolic changes occurring with menopause, individual risk profiles for decreased brain bioenergetics and cognitive decline can be created. Biomarker profiles could identify women at risk while also serving as indicators of efficacy of hormone therapy or other preventative interventions.


Finally, from perusing the available literature; I can conclude that the proper study to test HRT's effect on E4 carriers has yet to be conducted. I'd love to see a study on just E4 carriers, half of whom take bio-identical hormones, half of whom don't. THOSE results would be very telling.

This is beginning to smell a lot like the E4 fish oil debate ;) Remember how E4 carriers failed to benefit from fish oil in many studies? Just now, researchers are better understanding the mechanism and realizing that we many need more fish oil in order to get the same benefit as non E4 carriers. Given our already glucose deprived brains, I suspect we may also need estrogen replacement MORE than non E4 carriers.

circular
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Re: Hormone Replacement Therapy E4 Women

Postby circular » Wed Nov 05, 2014 6:36 pm

Good reasoning Stavia and Julien ... I mean Jiliegee I mean Juliegee!

It may also be that the RATIOS between hormones are a crucial factor, not just estrogens and progesterone but others along with. I'll bet the studies don't take account of this consistently?
ApoE 3/4 > Thanks in advance for any responses made to my posts.


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