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.
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.
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!)
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.
