ApoE4 and life expectancy/longevity

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Alma4567
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ApoE4 and life expectancy/longevity

Post by Alma4567 »

I have been looking up material on the influence of ApoE4 on average life expectancy, especially on South Europeans (given that is my family's heritage), and the evidence is CONFUSING and contradictory to say the least!

I have found studies with EVERY KIND of conflicting evidence - studies claiming APOE4 shortens life span by 5 years, studies claiming APOE4 has no influence on lifespan, studies claiming APOE4 only raises the risk of mortality in middle age, studies claiming APOE4 only raises risk of mortality at extreme age (>90), studies claiming APOE4 only affects mortality in men, studies claiming APOE4 only affects mortality in women, etc.

The evidence seems to be confusing and there seems to be no common consensus. Even certain studies have acknowledged the high degree of conflicting evidence. It seems every study has its own hypothesis and result that is wildly different to that of another.

As such, since certain studies are older than others, can someone who is more well-versed than me tell me if there is a common consensus and what it is? Does APOE4 shorten lifespan and if so by how much? Does it affect men more than women or vice versa?

Thanks
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Julie G
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Re: ApoE4 and life expectancy/longevity

Post by Julie G »

There is a lot of conflicting information out there, Alma. FWIW, some researchers describe ApoE4 as the "frailty gene." It is inversely correlated with longevity. We do have some remarkable members who are exceptions to that rule who serve as hopeful examples to us all. In general, women are more dramatically affected by ApoE4 in terms of AD risk and men may be affected more in terms of CVD risk. And, of course, dose matters; heterozygotes are less impacted than homozygotes.

Evidence suggests that ApoE4 can be advantageous in the right environment. As carriers of the ancestral allele, we represent a classic mismatch with modern civilization. By following a more ancestral example; eating real food less often and moving a lot, we hope to rectify that misalignment. Indeed, more and more evidence suggests that lifestyle changes can exert epigenetic influence over our supposedly negative gene offering us the best chance for longevity.
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Re: ApoE4 and life expectancy/longevity

Post by MAC »

Each one of us is n = 1 unique, so it's impossible to assess your individual all cause mortality/AD risk. Ancestral genetic makeup has a significant effect on E4 frequency and lifetime risk.

The literature on apoe/AD/CVD risk is VERY deep...it's the fundamental etiology of the disease that is desperately being sought.

Here is an amazing recent summary paper (2016) to give you deep insight into the lifetime risk questions you ask:

Age, APOE and Sex: Triad of Risk of Alzheimer’s Disease

The full paper (doi.org/10.1016/j.jsbmb.2016.03.012) is behind a paywall. Members in jurisdictions for which access to is legal may want to search http://sci-hub.bz/ for the paper there

Highlights

>The three greatest risk factors for Alzheimer’s disease are age, APOE-ε4 genotype and female sex.

> Convergence of these three risk factors, creates unique sex differences risk profiles for Alzheimer’s disease.

>The bioenergetic shift of the perimenopause to menopausal transition, unique to female, creates a risk event that likely exacerbates effect of APOE-ε4 positive females to thereby contribute to greater lifetime risk of Alzheimer’s disease in women.

>Increased risk of earlier onset of Alzheimer’s is evident in APOE-ε4 homozygote males whereas greater risk of later onset AD is evident in females.

> Years of life lost in men ε4 carriers are greater than in genotype-matched women

> Carrying one ε4 allele shifts the AD risk curve 5 years earlier. Two alleles shifts the AD risk curve by 10 years.
Screen Shot 2017-01-28 at 9.50.32 AM.png
Here is another summary paper:

APOE and Alzheimer disease: a major gene with semi-dominant inheritance
http://www.nature.com/mp/journal/v16/n9 ... 01152a.pdf

If you read this paper, you can see the cohort demographics and risks for men vs. women.
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Alma4567
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Re: ApoE4 and life expectancy/longevity

Post by Alma4567 »

Thanks MAC.

Of course every individual is different, but in the Western world, assuming the life expectancy for men/women is around 76 to 81 (respectively), what would you estimate the AVERAGE life expectancy for an APOE3/4 carrier would be?

What I'm trying to understand is - when people say APOE4 has a negative impact on life expectancy, is its general impact minor (i.e. 1-2 years), moderate (3-5 years) or high (5+ years)?
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Re: ApoE4 and life expectancy/longevity

Post by MAC »

Living in the "western world" with "southern European" genes?

What epigenetic lifestyle is being lived re metabolic syndrome, diet, smoking, alcohol, exercise, environmental exposure, social interaction, mood?

Impossible to answer, look at average male/female life expectancy and subtract for E4 allele/sex risk.
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Re: ApoE4 and life expectancy/longevity

Post by MAC »

Juliegee wrote:Evidence suggests that ApoE4 can be advantageous in the right environment
Julie et al, I found this passage in the 1st paper in my thread interesting, re E4/ketogenics:

"The contradictory effects of estrogenic agonists and an estrogen receptor antagonistin ApoE ε4 carriers suggest that the female ApoE ε4 brain is different that the ApoE 3 carriers. "We"? propose that one fundamental difference between the ApoE ε4 brain and Apoe 2 and 3 brains is in reliance of the ApoE ε4 brain on ketone bodies as a bioenergetic fuel. Reliance of the ApoE ε4 brain on ketone bodies as a bioenergetic fuel puts that brain at risk for utilization of its own white matter as fuel (29). In the female brain, estrogen activates the system biology of glucose metabolism while simultaneously suppressing the ketogenic system in brain thereby promoting brain reliance on glucose as its primary fuel to generate ATP (17, 28, 131-138). If the ApoE ε4 brain is a dual fuel dependent brain, being dependent upon glucose and ketone bodies, then suppression of the ketogenic system in the ApoE ε4 brain would result in reduction in a critical fuel to generate ATP. In the case ApoE 2 and 3 carriers, estrogenic activation of the glucose metabolism system and suppression of the ketogenic system is beneficial as estrogen is promoting and sustaining brain utilization of the primary fuel system glucose. In contrast, in a dual fuel dependent brain, one dependent upon both glucose and ketone bodies, suppression of the ketogenic pathway would put that brain at metabolic risk. Reliance of the ApoE ε4 brain on ketone bodies as a bioenergetic fuel is consistent with evidence from multiple laboratories demonstrating that ApoE ε4 carriers are glucose hypometabolic prior to decline in cognitive function (117, 139, 140)."

I haven't looked at the references, but this isn't a new (different) concept re female(?) risk and hypometabolism susceptibility in the E4 brain, and why we E4 (male/female) tend to practice LCHF?
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Re: ApoE4 and life expectancy/longevity

Post by SusanJ »

Alma, I don't have those figures, but perhaps someone else has come across them.

You'd have to find a study that looked all cause risk of death for E4s, because beyond dememtia and its complications, E4 puts us at higher risk for heart attack, too, along with complications for other diseases. This study looked at all cause risk, but doesn't talk about the results in terms of decrease in life span. You can always write to the authors to see if they can help you tease that out.

Apolipoprotein E Epsilon 4 Allele Interacts with Sex and Cognitive Status to Influence All-Cause and Cause-Specific Mortality Among US Older Adults
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3628727/
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Re: ApoE4 and life expectancy/longevity

Post by Julie G »

Apologies in advance for going off-topic, Alma. We tend to do that a lot ;) .

MAC, we've previously discussed Dr. Brinton's paper in our 40+ page thread on HRT. We specifically discussed whether bHRT might be a bad idea for E4 women because it may interfere with our brains preferential utilizations of KBs? Of course, we don't have answers. FWIW, many of us have found that the use of exogenous bHRT doesn't interfere with our ability to create KBs. By having a supply of both glucose and KBs as available to the brain perhaps we may be able to stave off the neuronal fuel shortage that occurs at midlife.

I found your reference to the paper below slightly frightening. Brinton et al hypothesize that the neuronal fuel shortage at menopause becomes so critical that we begin catabolizing our own white matter to create KBs. The hypothesis provides a strong argument for offsetting that fuel deficit early to protect the deterioration of our brains.

White Matter Lipids as a Ketogenic Fuel Supply in Aging Female Brain: Implications for Alzheimer's Disease
http://www.sciencedirect.com/science/ar ... 6415301924
Highlights

•Mitochondrial dysfunction activates mechanisms for catabolism of myelin lipids to generate ketone bodies for ATP production.
•Mechanisms leading to ketone body driven energy production in brain coincide with stages of reproductive aging in females.
•Sequential activation of myelin catabolism pathway during aging provides multiple therapeutic targets and windows of efficacy.

The mechanisms underlying white matter degeneration, a hallmark of multiple neurodegenerative diseases including Alzheimer's, remain unclear. Herein we provide a mechanistic pathway, spanning multiple transitions of aging, that links mitochondrial dysfunction early in aging with later age white matter degeneration. Catabolism of myelin lipids to generate ketone bodies can be viewed as an adaptive survival response to address brain fuel and energy demand. Women are at greatest risk of late-onset-AD, thus, our analyses in female brain address mechanisms of AD pathology and therapeutic targets to prevent, delay and treat AD in the sex most affected with potential relevance to men.
The authors hypothesize that this mechanism may have potential relevance for men as well. In the past, I've tried to dive into that literature but came up with more questions than answers. Does testosterone help deliver glucose to the brain? Can the andropause that males experience affect men similarly? Here's a paper that dances around the topic.
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Re: ApoE4 and life expectancy/longevity

Post by MAC »

Yeah I thought it was a different KB theory I have not come across before.

Ancestrally though...would we be here if this theory were root cause?

Not looked at it from male perspective.
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Re: ApoE4 and life expectancy/longevity

Post by sahara »

This is interesting: Polygenic Propensity for Longevity, APOE-ε4 Status, Dementia Diagnosis, and Risk for Cause-Specific Mortality: A Large Population-Based Longitudinal Study of Older Adults
https://academic.oup.com/biomedgerontol ... 73/7223000

Accept my apology if it's been cited on another thread.
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