APOΕ4 Lowers Energy Expenditure and Impairs Glucose Oxidation by Increasing Flux through Aerobic Glycolysis

[BrianR]

Open access preprint: https://www.biorxiv.org/content/10.1101 ... 9.345991v2

bioRxiv posted October 20, 2020.
APOE4 Lowers Energy Expenditure and Impairs Glucose Oxidation by Increasing Flux through Aerobic Glycolysis
Brandon C Farmer, ..., Lance A. Johnson
doi: 10.1101/2020.10.19.345991

For those who like to speculate, the study's findings provide a neat "just so" story in which APOE4 was adaptive for our hunting & gathering ancestors, who were subject to periodic food shortages, which would have been particularly acute when burdened by a significant parasite load (as was most likely the case). This would have been especially true for females going through the energy demands of pregnancy.

I guess the takeaway is that we want to find ways to improve oxygen consumption in our brains. (Which is something that has already been discussed a lot in the group.)

Abstract
Cerebral glucose hypometabolism is consistently observed in individuals with Alzheimer’s disease (AD), as well as in young cognitively normal carriers of theΕ4allele of Apolipoprotein E (APOE), the strongest genetic predictor of late-onset AD. While this clinical feature has been described for over two decades, the mechanism underlying these changes in cerebral glucose metabolism remains a critical knowledge gap in the field.
...
Metabolic phenotyping of E4 astrocytes showed elevated glycolytic activity, decreased oxygen consumption, blunted oxidative flexibility, and a lower rate of glucose oxidation in the presence of lactate. Together, these cellular findings suggested an E4 associated increase in aerobic glycolysis (i.e. the Warburg effect). ...

... young female E4 carriers showed a striking decrease in energy expenditure compared to non-carriers. This decrease in energy expenditure was primarily driven by a lower rate of oxygen consumption, and was exaggerated following a dietary glucose challenge. Further, the stunted oxygen consumption was accompanied by markedly increased lactate in the plasma of E4 carriers, and a pathway analysis of the plasma metabolome suggested an increase in aerobic glycolysis. Together, these results suggest astrocyte, brain and system-level metabolic reprogramming in the presence of APOE4, a ‘Warburg like’ endophenotype that is observable in young humans decades prior to clinically manifest AD.

[Tincup]

Perhaps suggest that higher level of ketones might help offset this from an energetic perspective.

More oxygen might also be helpful. A higher CO2 tolerance leading to higher serum CO2 and lower serum pH can shift the Oxygen–hemoglobin dissociation curve rightward (based on the Bohr effect). Various breathing training approaches can be used to increase CO2 tolerance. See Oxygen Advantage A lInk to list of books on the topic. To encourage this, I've taped my mouth shut at night for years so that I breathe through my nose at night and always breathe through my nose during the day diaphragmatically, even when skiing hard at 13,000' (3,960 m) elevation. "Shut Your Mouth" book. "Snoring" book

[Julie G]

Perhaps suggest that higher level of ketones might help offset this from an energetic perspective.

More oxygen might also be helpful. A higher CO2 tolerance leading to higher serum CO2 and lower serum pH can shift the Oxygen–hemoglobin dissociation curve rightward (based on the Bohr effect). Various breathing training approaches can be used to increase CO2 tolerance. See Oxygen Advantage LInk to list of books on the topic.

I was thinking exactly the same, Tincup. And, no surprise, living ancestrally —with plenty of exercise and fasting—ought to provide both higher ketones and oxygen. I also wondered what researchers would find if they studied an E4 population who did just that, harkening back to our ongoing theme that suggests E4 is only a disadvantage when mismatched with modern living.

[Bailey]

This article is fascinating but the jargon is way over my head. Can someone provide a quick summary of the key take-aways in layman’s terms please?

[Tincup]

This article is fascinating but the jargon is way over my head. Can someone provide a quick summary of the key take-aways in layman’s terms please?

Even in their 30's, E4 carriers can show reduced brain glucose metabolism. As this worsens over time, an energy crisis can occur in the brain. From the paper, "This decrease in energy expenditure was primarily driven by a lower rate of oxygen consumption, and was exaggerated following a dietary glucose challenge. " The bolded section (that I bolded) tells you that high ultra processed carb diet is likely something that will increase this, especially in E4's. Hence not advised.

So, staying in mild ketosis, as Dr. Bredesen recommends, can provide the brain with an alternative fuel that uses a different pathway. I've been keto adapted since 2009. Also paying attention to oxygen at night and in general as I posted above. Mouth taping may seem unusual, but quite a few people with mild to moderate sleep apnea have mitigated it with mouth taping. In my case, if I wear a recording beat to beat heart rate monitor, I can see apnea patterns in the heart rate, if I'm not taped. The graph is from last night, from a ring that measures heart rate and SpO2 (blood oxygen saturation). My average was 95%, which is not bad as I live at 5,500' (1, 675 m) elevation and SpO2 will decrease with elevation. I pay a lot of attention to breathing.

Screenshot 2020-10-23 at 11.12.45.jpg

[Bailey]

This article is fascinating but the jargon is way over my head. Can someone provide a quick summary of the key take-aways in layman’s terms please?

Even in their 30's, E4 carriers can show reduced brain glucose metabolism. As this worsens over time, an energy crisis can occur in the brain. From the paper, "This decrease in energy expenditure was primarily driven by a lower rate of oxygen consumption, and was exaggerated following a dietary glucose challenge. " The bolded section (that I bolded) tells you that high ultra processed carb diet is likely something that will increase this, especially in E4's. Hence not advised.

So, staying in mild ketosis, as Dr. Bredesen recommends, can provide the brain with an alternative fuel that uses a different pathway. I've been keto adapted since 2009. Also paying attention to oxygen at night and in general as I posted above. Mouth taping may seem unusual, but quite a few people with mild to moderate sleep apnea have mitigated it with mouth taping. In my case, if I wear a recording beat to beat heart rate monitor, I can see apnea patterns in the heart rate, if I'm not taped. The graph is from last night, from a ring that measures heart rate and SpO2 (blood oxygen saturation. My average was 95%, which is not bad as I live at 5,500' (1, 675 m) elevation and SoO2 will decrease with elevation. I pay a lot of attention to breathing.

Screenshot 2020-10-23 at 11.12.45.jpg

Thank you Tincup! I’m a 35 year old Apoe4/4 and recently started transitioning into mild ketosis. This article really drives home the importance of low carb diets. I tried reading the full paper but many terms are over my head. I need a biochemistry crash course!

I just got the new iWatch and I’m tracking my oxygen while I sleep. So far so good! I’m hoping to learn more about how HBOT might help get oxygen to the brain...Possibly a useful therapy for Apoe4s.

[Tincup]

Thank you Tincup! I’m a 35 year old Apoe4/4 and recently started transitioning into mild ketosis. This article really drives home the importance of low carb diets. I tried reading the full paper but many terms are over my head. I need a biochemistry crash course!

I just got the new iWatch and I’m tracking my oxygen while I sleep. So far so good! I’m hoping to learn more about how HBOT might help get oxygen to the brain...Possibly a useful therapy for Apoe4s.

I've related this story before: I'm an only child (E3/4) of a brilliant mother who passed with dementia. Mom got a physics degree in 1948 (age 22) & managed the DOD's (Defense Department) first attempts at missile tracking with computers. At age 60, she returned and got a degree in computer science. She would tell me she was much mentally slower than she was at nineteen. As she was setting the curve in her classes, I wasn't worried. Fast forward to my investigating my ApoE4 status (I have no idea if she was the parent I got my 4 from). I learned that 4's can exhibit inhibited cerebral glucose processing as early as their 3rd decade, years before any mental deficits occur. This may explain my mother's comments. I'm 65 now. My wife is 4/4 and contributes here, too.

Don't worry about the terminology. Keep reading here and elsewhere, and you will accumulate the vocabulary over time.

HBOT might be useful, but (from my perspective), you want something all the time, if possible, not episodic.

[Renlets]

This article is fascinating but the jargon is way over my head. Can someone provide a quick summary of the key take-aways in layman’s terms please?

Hi Bailey,
Welcome to the Apoe4.info forum, we glad to see you are already engaging with the information on the site as well as the discussions with Tincup.

I just wanted to take the time to welcome you and point out just a few areas that may be of interest to you or help you navigate the site better. The Primer is one of our most informative area written by one of our member physicians, with an APOE4 gene. I will encourage you to go through this area for more easy to understand lifestyle guidelines. We also have a How-to-guide that will give you details of how to navigate the site better. For example, it will help you know how to tag people, message them privately on the site or follow already existing discussions. The wiki is another area full of articles on various topics of interest, and you can use it to research further. I hope these tools come handy as you engage with the information on the site.

Once more welcome, looking forward to more of your engagement on the forum

Kind regards
RenLets

[floramaria]

More oxygen might also be helpful. A higher CO2 tolerance leading to higher serum CO2 and lower serum pH can shift the Oxygen–hemoglobin dissociation curve rightward (based on the Bohr effect). Various breathing training approaches can be used to increase CO2 tolerance.

Thanks for these resources . I’ve started reading “Shut Your Mouth”.
It seems to have some overlap with Qigong training. In Qigong, Breathing is done only through the nose. We are instructed that the breath should be “Slow, long, thin, soft and even”. Relaxed breathing is key. Here is a quote from the book “Tai Chi Essentials” , by Andrew Townsend, In a section addressing reducing breathing through deep, meditative relaxation :
“ As you reduce your respiration rate to one or two breaths per minute you approach the level of breathing referred to by the Chinese as “tortoise breathing”. Because of their slow metabolism and very slow breathing, tortoises live for many years. In fact, the tortoise is the symbol of longevity in China. There is a Chinese folk wisdom that asserts that each individual is allocated a certain number of breaths in his or her lifetime. The faster one breathes, the sooner one will reach his or her final breath “

[Tincup]

It seems to have some overlap with Qigong training. In Qigong, Breathing is done only through the nose. We are instructed that the breath should be “Slow, long, thin, soft and even”. Relaxed breathing is key. Here is a quote from the book “Tai Chi Essentials” , by Andrew Townsend, In a section addressing reducing breathing through deep, meditative relaxation :
“ As you reduce your respiration rate to one or two breaths per minute you approach the level of breathing referred to by the Chinese as “tortoise breathing”. Because of their slow metabolism and very slow breathing, tortoises live for many years. In fact, the tortoise is the symbol of longevity in China. There is a Chinese folk wisdom that asserts that each individual is allocated a certain number of breaths in his or her lifetime. The faster one breathes, the sooner one will reach his or her final breath “

Yes, much overlap with eastern approaches. Nasal breathing directs the breath to the lowest lung lobes, Also the nose is a reservoir of nitric oxide (humming with nose breathing can increase nitric oxide by ~15 times). So yes slow, relaxed with a low breathing volume.

On the other side is Wim Hof breathing. This includes 30-40 hyperventilation breaths followed by a long breath hold. This creates a more basic (higher pH) serum. This is a good hormetic approach, not all day. I do one to two 10-15 minute rounds of this a day and the rest of the time I breath very light, diaphragmatically and slow through the nose - for a more acidic pH. It has helped my autoimmune nasal congestion. Website

Breathing instructor, Patrick McKeown, has an mp3 download for this light relaxed breathing.

Russian doctor Buteyko developed a simple test for CO2 tolerance, called "Control Pause." An explanation. also here. Essentially breathing normally through the nose, on a normal exhale hold your breath out. Time from when you start holding out till you feel your first urge to breath (this is NOT a maximal breath hold).

Dr. Buteyko said ideal was 60 seconds. Pretty good is 40 seconds. Many are much shorter. Here is his chart


One of the best breathing books is by James Nestor, Breath This is not so much a "how to" book, but a description of what is possible. Nestor interview with UK doc, Rangan Chattergee. Patrick McKeown interview with Chattergee. Wim Hof interview with Chattergee.

Mckeown has a great how to book.
in addition to the ones I linked in the post above.

A number of exercises from James Nestor's site.