Ketosis for APOE ε4s

Insights and discussion from the cutting edge with reference to journal articles and other research papers.
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Brian4
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Ketosis for APOE ε4s

Post by Brian4 »

Hi everyone,

I sort of fell into low-carb eating because carbs were giving me gut problems. Then I discovered I really enjoy eating like a chipmunk. :) I get around 94% of my calories from nuts; the rest, from low-starch veggies (and DHA supplements, which add up, calorie-wise!). And most of the nuts I eat are the low-carb ones.

I started hearing about the benefits of ketosis a while back, looked at the research, and concluded that ketosis might not help APOE-ε4s much.

Some more recent papers speculate that APOE-ε4s might benefit a bit though, and/or that benefits might take more time to show up. But there's no solid evidence for that. The results of the studies taken as a whole are mixed, and most of the studies have serious flaws. There is unfortunately literally zero quality evidence pointing one way or another. I'm not opposed to speculating based on mechanism – we have to make decisions in the absence of good science all the time! – but even based on likely mechanisms of ketone generation and metabolism, I don't see a reason to believe that ketosis will help ε4s, especially not homozygotes.

But here's a hopeful review, contending that APOE-ε4 carriers might respond, but that it just takes longer:

https://www.ncbi.nlm.nih.gov/labs/pmc/a ... MC7666893/

But serious studies showing cognitive improvement – the relevant endpoint – don't seem to exist

And there are of course differences between inducing ketosis via energy restriction, and inducing it via exogenous ketones, or a low-carb diet.

Another concern is that heterozygotes and homozygotes are pooled in all the studies so far published (that I've been able to find). Given that the effects of ApoE are "dose dependent", it might only be the heterozygotes who are getting (possibly minimal) benefit.

I think when the dust settles, we might find:

- Non-carriers benefit tremendously from ketosis.
- Carriers of one ε4 allele benefit less, but enough (because they do have one ε3 or ε2) to make it worth it.
- Homozygotes (the people we most need to help!) don't benefit at all, or only very minimally.

A good bet-hedging strategy for ε4s might be to induce ketosis through dietary restriction of some kind (fasting, etc.), since there's good reason to believe that dietary restriction would slow the onset of dementia, since it likely slows the rate of aging. But there, too, we only have indirect evidence (tons of it, but still indirect).

Anyway, I know a lot of people here think that ketosis can help APOE-ε4s. Can someone explain why? The more reasons I have for continuing to eat like a chipmunk, the better.

Thanks!
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Re: Ketosis for APOE ε4s

Post by Julie G »

Anyway, I know a lot of people here think that ketosis can help APOE-ε4s. Can someone explain why?
Nice to see you posting! As you know, so much of ApoE4 science remains unsettled leaving us to rely on signals vs. conclusive evidence. Richard Isaacson does a nice job of covering the best evidence for E4s with recommendations in this paper, including a section on ketosis.
Finally, while no long-term prospective trials for the potential of dietary interventions to prevent AD in ApoE4 carriers exists, a recent human study observed that ketogenic diets and βhB improved a newly established marker of brain aging, brain network stability, whereas carbohydrate-rich diets impaired brain network stability [99]. Thus, mechanisms and emerging data suggest that adopting a lifestyle on the spectrum of low-glycemic index, low-carbohydrate, and ketogenic diets might help to protect against insulin resistance, inhibit pathological inflammatory processes (NLRP3 and CypA-NFκB-MMP9), and be an overall effective neuroprotective strategy in carriers of ApoE4.
And, of course, there are multiple E4 case studies showing benefit with ketosis

https://pubmed.ncbi.nlm.nih.gov/31336463/

https://pubmed.ncbi.nlm.nih.gov/29706312/

https://pubmed.ncbi.nlm.nih.gov/30923733/

https://pubmed.ncbi.nlm.nih.gov/32305654/
A good bet-hedging strategy for ε4s might be to induce ketosis through dietary restriction of some kind (fasting, etc.), since there's good reason to believe that dietary restriction would slow the onset of dementia, since it likely slows the rate of aging. But there, too, we only have indirect evidence (tons of it, but still indirect).
Agree, as long as folks stay weight stable and strong. Failing to do so appears to increase the risk of cognitive decline. FWIW, I like to combine a long daily fast with exercise to get into ketosis. This roughly mimics the lifestyle of our E4 hunter-gatherer ancestors (as well as modern day Tsimane), who likely went long periods without food and had to work hard to find it.
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Re: Ketosis for APOE ε4s

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Brian4 wrote:Hi everyone,
Julie G wrote:
There is also Randomized crossover trial of a modified ketogenic diet in Alzheimer’s disease. This paper shows improvement in functioning and quality of life with a 12 week intervention of a modified ketogenic diet, and some non-significant improvement in cognition, though the authors do speculate that ApoE4 carriers benefited less than others.
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Re: Ketosis for APOE ε4s

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Brian4 wrote: But here's a hopeful review, contending that APOE-ε4 carriers might respond, but that it just takes longer:

https://www.ncbi.nlm.nih.gov/labs/pmc/a ... MC7666893/

But serious studies showing cognitive improvement – the relevant endpoint – don't seem to exist
What the studies in this review seem to be saying (collectively) is that people with similar level of ketosis respond similarly regardless of ApoE variants, it just takes longer or more of an intervention to get ApoE4 carriers into ketosis. If so then at least the encouraging news is that if we get to measurable ketosis we are in the right direction and will benefit. Since measuring ketones is currently feasible we can tell if we are on the right path nutritionally speaking, and if not, we have the means to find out if any additional changes we employ are helpful.
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Re: Ketosis for APOE ε4s

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The ApoE4/Ketosis story is still unfolding, but it’s somewhat reminiscent of the ApoE4/DHA story — also still unfolding. Almost a decade ago, when I began wading through the science, researchers noted that E4 carriers didn’t appear to cognitively benefit from DHA like other APOE genotypes. We had lower blood levels after consuming the same amount, etc. This lead some in the research community to assume that E4 carriers shouldn’t use DHA. In fact some radicals took this a step further and proposed that E4 carriers should only use alpha linolenic acid (ALA) the precursor to DHA.

The current evidence, however, has shifted towards the idea that E4 carriers actually need higher amounts of DHA as we appear to preferentially metabolize it. In this instance, what helps other APOE genotypes also helps E4 carriers, we just need a bit more assistance. Given the current state of evidence, I’m guessing that the ketosis story will play out similarly.
What the studies in this review seem to be saying (collectively) is that people with similar level of ketosis respond similarly regardless of ApoE variants, it just takes longer or more of an intervention to get ApoE4 carriers into ketosis. If so then at least the encouraging news is that if we get to measurable ketosis we are in the right direction and will benefit. Since measuring ketones is currently feasible we can tell if we are on the right path nutritionally speaking, and if not, we have the means to find out if any additional changes we employ are helpful.
I completely agree. It's easy enough to measure ketones and other associated biomarkers (glycemic markers, advanced lipids, oxLDL, etc.) As long as the big picture is moving towards health, this strategy doesn't appear to carry a lot of risk. That said, there are multiple strategies for achieving ketosis, the method one choses will likely play a big role in how this strategy affects overall health and ultimately cognition. And, my guess is that E4 carriers will need to employ this strategy a bit differently than other APOE genotypes.

Dr. Bredesen and I are doing a facebook Live on "Ketosis for Cognition" tomorrow (11/4) at 2pm PT. Join us on his Facebook page, Dale Bredesen, MD. if you can. We'll take a deep dive into the why, the how, and much more.
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Re: Ketosis for APOE ε4s

Post by Julie G »

Julie G wrote:The ApoE4/Ketosis story is still unfolding, but it’s somewhat reminiscent of the ApoE4/DHA story — also still unfolding. Almost a decade ago, when I began wading through the science, researchers noted that E4 carriers didn’t appear to cognitively benefit from DHA like other APOE genotypes. We had lower blood levels after consuming the same amount, etc. This lead some in the research community to assume that E4 carriers shouldn’t use DHA. In fact some radicals took this a step further and proposed that E4 carriers should only use alpha linolenic acid (ALA) the precursor to DHA.

The current evidence, however, has shifted towards the idea that E4 carriers actually need higher amounts of DHA as we appear to preferentially metabolize it. In this instance, what helps other APOE genotypes also helps E4 carriers, we just need a bit more assistance. Given the current state of evidence, I’m guessing that the ketosis story will play out similarly.
What the studies in this review seem to be saying (collectively) is that people with similar level of ketosis respond similarly regardless of ApoE variants, it just takes longer or more of an intervention to get ApoE4 carriers into ketosis. If so then at least the encouraging news is that if we get to measurable ketosis we are in the right direction and will benefit. Since measuring ketones is currently feasible we can tell if we are on the right path nutritionally speaking, and if not, we have the means to find out if any additional changes we employ are helpful.
I completely agree. It's easy enough to measure ketones and other associated biomarkers (glycemic markers, advanced lipids, oxLDL, etc.) As long as the big picture is moving towards health, this strategy doesn't appear to carry a lot of risk. That said, there are multiple strategies for achieving ketosis, the method one chooses will likely play a big role in how this strategy affects overall health and ultimately cognition. And, my guess is that E4 carriers will need to employ this strategy a bit differently than other APOE genotypes.


Dr. Bredesen and I are doing a facebook Live on "Ketosis for Cognition" tomorrow (11/4) at 2pm PT. Join us on his Facebook page, Dale Bredesen, MD. if you can. We'll take a deep dive into the why, the how, and much more.
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Re: Ketosis for APOE ε4s

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Quantifier wrote: What the studies in this review seem to be saying (collectively) is that people with similar level of ketosis respond similarly regardless of ApoE variants, it just takes longer or more of an intervention to get ApoE4 carriers into ketosis. If so then at least the encouraging news is that if we get to measurable ketosis we are in the right direction and will benefit. Since measuring ketones is currently feasible we can tell if we are on the right path nutritionally speaking, and if not, we have the means to find out if any additional changes we employ are helpful.
Well, there's one well-done study (though the authors have a conflict of interest) showing a slight improvement in ε4 carriers according to one measure (MMSE) after three and a half months. That's promising, to be sure.

Measuring ketones is easy, yes, but it would be helpful to measure what is in question: cognitive changes.

Julie, I hope you're right about where the research will ultimately end up! Some well-designed studies are now underway, and we should know more by mid-2023. Unfortunately, I'm unaware of any study underway sufficiently large to examine the effects on homozygotes, so that might remain an open question for some time to come.

I have a conflict tomorrow but I will try to switch my other meeting to be able to tune in to you and Dr. Bredesen. Thanks for setting that up!

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Re: Ketosis for APOE ε4s

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In Julie's linked case studies, they all cleaned up their metabolism to a significant degree. Hard to say if ketones, per say, were the cause of the improvement, or just the improved metabolism. In any case, I find it hard to argue against cleaning up your metabolism.

I know there are some n=1 reports of people who perceive that they need a modest level of serum BHB (say 1 mmol/L) to function well. I think Julie is in this category. My 4/4 wife & I are in the group who can't subjectively tell the difference in our mental function between 0 & 8 mmol/L. However, I look at a measurable level of BHB as an indication of a low insulin level, indicating metabolism is reasonably healthy. I've been "keto-adapted" since Oct 2009 and 99.9% of the time will test measurable serum BHB on a morning test.
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Re: Ketosis for APOE ε4s

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Hey Tincup,

I agree: it wouldn't make sense to question the value of getting one's metabolic house in order.

Metabolic syndrome is rare in blue zones. Most of these people eat a lot of carbs, in many cases a huge amount of carbs, but they exercise a lot. There are many paths to healthy metabolism.

And it should be noted that the blue zones are typically ε4-poor (since they're mostly in east Asia and southern Europe). So what works for non-ε4 carriers might not work for ε4s. (Or the absence of blue zones in ε4-heavy parts of the world might just be a painful reminder that APOE-ε4 is a "shortgevity" allele.)

I used to eat a low-fat diet, but I was calorie restricted (and still am).

I've been eating in a six-or-so–hour window, starting in the morning, with the last meal very light, for a while now. I wake with BHB around 1.8, and by 19:30 or so it's back up to 1.8. I fast (modified fast: 300–500 calories/day) one day or sometimes several days, pretty regularly. I don't feel any worse or better than when I grazed carbs (aside from my gut, which likes the chipmunk diet). I think any improvement in health I've experienced is from the energy-intake reduction, which has multiple effects (ketosis being one of them).

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Re: Ketosis for APOE ε4s

Post by Julie G »

Great discussion!
I know there are some n=1 reports of people who perceive that they need a modest level of serum BHB (say 1 mmol/L) to function well. I think Julie is in this category. My 4/4 wife & I are in the group who can't subjectively tell the difference in our mental function between 0 & 8 mmol/L
To clarify, when I was insulin resistant (and experiencing frequent episodes of hypoglycemia), I definitely felt cognitively sharper and more bio-energetically stable in ketosis. Now that my metabolic flexibility is restored, I feel the same whether I'm burning glucose or ketones. I still choose to get into ketosis on a daily basis via a long daily fast + exercise to help me remain metabolically flexible.
Metabolic syndrome is rare in blue zones. Most of these people eat a lot of carbs, in many cases a huge amount of carbs, but they exercise a lot. There are many paths to healthy metabolism.
I completely agree that our overriding goal is to avoid metabolic syndrome. I also agree that there are multiple paths to get there. Dr. Bredesen's recommendation to use our KetoFLEX 12/3 diet + long daily fast + daily exercise is for those who are experiencing either insulin resistance or symptoms of cognitive decline with ketosis as a short term goal and restoration of metabolic flexibility as the longer term goal. That said, it's not a bad plan for anyone.
I don't feel any worse or better than when I grazed carbs (aside from my gut, which likes the chipmunk diet).
FWIW, many people report the same gut health improvement when giving up grains which can be quite inflammatory for multiple reasons.
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