Ketone Bodies Clear Damaged Proteins in the Brain

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TheresaB
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Ketone Bodies Clear Damaged Proteins in the Brain

Post by TheresaB »

It’s already well known that ketones can augment glucose in providing fuel to the brain, especially for APOE4s who have impaired brain glucose uptake. We also know ketones also offer a number of other benefits for the brain, gut, inflammation, metabolic health, etc., now here’s another one.

As published by Neuroscience News yesterday, 2 December 2024, Ketone Bodies Clear Damaged Proteins in the Brain
Summary: Ketone bodies, known for their role in energy metabolism during fasting, have been shown to directly interact with damaged proteins in the brain, aiding their clearance through autophagy. Researchers discovered that the ketone body β-hydroxybutyrate alters the solubility of misfolded proteins, facilitating their removal and reducing pathological aggregation.
Tests in mouse models of Alzheimer’s and aging confirmed these effects, with treated animals showing improvements in protein quality control and brain health. This breakthrough provides a new metabolic link to aging and neurodegeneration, offering a potential pathway for therapeutic applications.
Key Facts
• Ketone bodies directly bind to misfolded proteins, enhancing their clearance via autophagy.
• Mice treated with ketone esters displayed reduced aggregation of insoluble brain proteins.
• Similar metabolites tested showed effects equal to or better than β-hydroxybutyrate.
Here’s the original paper this article is based on:
β-hydroxybutyrate is a metabolic regulator of proteostasis in the aged and Alzheimer disease brain
-Theresa
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Brian4
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Re: Ketone Bodies Clear Damaged Proteins in the Brain

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In human APOE ε4 carriers, ketones might not help so much:

https://pmc.ncbi.nlm.nih.gov/articles/PMC7297981/
Older APOE4 carriers with CI also show resistance to improvement from a ketogenic diet. Two interventions demonstrated that APOE4 carriers do not benefit from a ketogenic diet (Reger et al., 2004; Henderson et al., 2009). In one of these interventions (Henderson et al., 2009), 152 participants with mild AD were randomized to AC-1202 to rapidly elevate serum ketone bodies or placebo. The intervention resulted in modest differences in ADAS-Cog scores compared to the placebo. However, the effects were only seen in APOE4 negative subjects who were compliant with the intervention. Understanding the type of diet that the brain of older APOE4 carriers utilize as fuel would be a priority for future studies.
We need some well-designed trials to look at this question carefully.

N. Norwitz and others have argued that a ketogenic diet would be good for APOE ε4 carriers, it's just that we need more time to adapt. But the evidence is still thin, and I think it's partly wishful thinking. (This is one of the many reasons why I'm now focused on gene therapy. Fix the most upstream source of the risk!)
ε4/ε4 (for now).
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TheresaB
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Re: Ketone Bodies Clear Damaged Proteins in the Brain

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Brian4 wrote: Wed Dec 04, 2024 6:00 am In human APOE ε4 carriers, ketones might not help so much:

https://pmc.ncbi.nlm.nih.gov/articles/PMC7297981/
Older APOE4 carriers with CI also show resistance to improvement from a ketogenic diet. Two interventions demonstrated that APOE4 carriers do not benefit from a ketogenic diet (Reger et al., 2004; Henderson et al., 2009). In one of these interventions (Henderson et al., 2009), 152 participants with mild AD were randomized to AC-1202 to rapidly elevate serum ketone bodies or placebo. The intervention resulted in modest differences in ADAS-Cog scores compared to the placebo. However, the effects were only seen in APOE4 negative subjects who were compliant with the intervention. Understanding the type of diet that the brain of older APOE4 carriers utilize as fuel would be a priority for future studies.
We need some well-designed trials to look at this question carefully.

N. Norwitz and others have argued that a ketogenic diet would be good for APOE ε4 carriers, it's just that we need more time to adapt. But the evidence is still thin, and I think it's partly wishful thinking. (This is one of the many reasons why I'm now focused on gene therapy. Fix the most upstream source of the risk!)
I'll have to investigate these findings later (gotta go right now), but from an ancestral lifestyle standpoint, this makes no sense. What kind of ketogenic diet was employed for these findings? A high saturated fat, high red meat, no fasting/autophagy ketogenic diet that many seem to equate with a ketogenic diet now-a-days? Or a more ancestral ketogenic diet where fasting and a non-sedentary lifestyle encouraged ketones along with a varied diet with plant and animal food sources.
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Re: Ketone Bodies Clear Damaged Proteins in the Brain

Post by usernamebetty »

I believe the study, Brian4 is referencing (Henderson, et al., 2009) involved supplementation with what is essentially MCT oil, which doesn't result in the same degree of ketosis one would get from a ketogenic diet:

https://pmc.ncbi.nlm.nih.gov/articles/PMC8073598/

"For example, one study found that administration of the ketogenic substance, caprylic acid, to individuals with diagnosed AD led to improvements only in non-carriers [81]. There are at least two important caveats to this finding. First, the degree of ketosis induced was light and temporary. Even directly post-supplementation, βhB levels only reached 0.4 mM, which is short of nutritional ketosis and may not have been sufficient to compensate for the presumably larger impairment in glucose metabolism in ApoE4 carriers. By contrast, a ketogenic diet has been shown to improve cognition in ApoE4 context [79]. "

On this one I would go with the most recent research supporting ketogenic diets for APOE4.
Last edited by usernamebetty on Wed Feb 12, 2025 11:56 am, edited 1 time in total.
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Re: Ketone Bodies Clear Damaged Proteins in the Brain

Post by rdpchef »

usernamebetty wrote: Wed Feb 12, 2025 11:53 am I believe the study, Brian4 is referencing (Henderson, et al., 2009) involved supplementation with what is essentially MCT oil, which doesn't result in the same degree of ketosis one would get from a ketogenic diet:

https://pmc.ncbi.nlm.nih.gov/articles/PMC8073598/

"For example, one study found that administration of the ketogenic substance, caprylic acid, to individuals with diagnosed AD led to improvements only in non-carriers [81]. There are at least two important caveats to this finding. First, the degree of ketosis induced was light and temporary. Even directly post-supplementation, βhB levels only reached 0.4 mM, which is short of nutritional ketosis and may not have been sufficient to compensate for the presumably larger impairment in glucose metabolism in ApoE4 carriers. By contrast, a ketogenic diet has been shown to improve cognition in ApoE4 context [79]. "

On this one I would go with the most recent research supporting ketogenic diets for APOE4.
Hi Usernamebetty,

Thank you for joining in the conversation about Ketone bodies and adding a link to an NIH resource, we appreciate that. I'm a welcoming intern on the forum and want to point out some resources that may be helpful to you on the forum.

If you haven't already, it would be a great idea to first take a look at our Primer. It is an incredible resource of information about the biochemistry of ApoE4. It offers researched-based prevention strategies and was written by a practicing M.D. with ApoE4. Do not become overwhelmed with all the information. Sometimes it is best to slowly read through it, decide which section resonates with you, and focus on that area first. Remember that small changes can make a big difference to brain health.

The How-To Guide will help you learn how to navigate this site. It includes topics such as navigating the forum, private messaging, and searching.

You can find other members' experiences in Our Stories.
If you haven't already and feel comfortable sharing your story, we'd love to learn more about you.

I'm so glad you have joined us on this site. Please feel free to reach out anytime with questions or if you just need support. We are here for you and welcome your posts and replies to others posts.

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