Effects of β-hydroxybutyrate on cognition in memory-impaired adults

Reger, Mark A.; Henderson, Samuel T.; Hale, Cathy; Cholerton, Brenna; Baker, Laura D.; Watson, G. Stennis; Hyde, Karen; Chapman, Douglas; Craft, Suzanne

doi:10.1016/s0197-4580(03)00087-3

Cited by 450 publications

(454 citation statements)

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“…The rapid (90 min) improvement seen in cognitive tasks suggests that the effect is driven by enhanced neuronal metabolism. 54 A longer, 90-day dosing study has shown similar positive results in E4(Ϫ) subjects (Henderson et al, manuscript in preparation). Importantly, the level of ketosis achieved in the Reger et al 54 study is considerably lower then those used in infusion studies, and lower than levels predicted for efficacy based on theoretical arguments.…”

Section: Ketosis and Admentioning

confidence: 84%

“…54 A longer, 90-day dosing study has shown similar positive results in E4(Ϫ) subjects (Henderson et al, manuscript in preparation). Importantly, the level of ketosis achieved in the Reger et al 54 study is considerably lower then those used in infusion studies, and lower than levels predicted for efficacy based on theoretical arguments. 22 This suggests that easily achievable levels of ketosis may be beneficial to the AD patient in the absence of dietary changes.…”

Section: Ketosis and Admentioning

confidence: 84%

“…In the Reger et al 54 study, efficacy was most notable in E4(-) subjects. Interestingly, APOE4 effects have been noted in other studies targeting the insulin pathway as a treatment for AD.…”

Section: Ketosis and Admentioning

confidence: 92%

“…Reger et al 54 conducted a crossover study to examine the effects of acute elevation of serum KB levels on cognitive performance in 20 mild to moderate probable AD subjects. A single, 40 g dose of MCT induced a significant elevation (10-fold) of BHB to 0.5 mM after 2 hours.…”

Section: Ketosis and Admentioning

confidence: 99%

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Ketone Bodies as a Therapeutic for Alzheimer's Disease

Henderson¹

2008

Neurotherapeutics

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Summary: An early feature of Alzheimer's disease (AD) is region-specific declines in brain glucose metabolism. Unlike other tissues in the body, the brain does not efficiently metabolize fats; hence the adult human brain relies almost exclusively on glucose as an energy substrate. Therefore, inhibition of glucose metabolism can have profound effects on brain function. The hypometabolism seen in AD has recently attracted attention as a possible target for intervention in the disease process. One promising approach is to supplement the normal glucose supply of the brain with ketone bodies (KB), which include acetoacetate, ␤-hydroxybutyrate, and acetone. KB are normally produced from fat stores when glucose supplies are limited, such as during prolonged fasting. KB have been induced both by direct infusion and by the administration of a high-fat, low-carbohydrate, low-protein, ketogenic diets. Both approaches have demonstrated efficacy in animal models of neurodegenerative disorders and in human clinical trials, including AD trials. Much of the benefit of KB can be attributed to their ability to increase mitochondrial efficiency and supplement the brain's normal reliance on glucose. Research into the therapeutic potential of KB and ketosis represents a promising new area of AD research.

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Section: Ketosis and Admentioning

confidence: 84%

Section: Ketosis and Admentioning

confidence: 84%

Section: Ketosis and Admentioning

confidence: 92%

Section: Ketosis and Admentioning

confidence: 99%

See 2 more Smart Citations

Ketone Bodies as a Therapeutic for Alzheimer's Disease

Henderson¹

2008

Neurotherapeutics

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298

120

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“…In addition, there are studies indicating that ketone bodies have little effect on AD pathology, despite benefits on motor performance [57,66]. Two early proof-of-concept clinical studies, investigating ketone bodies for mild-to-moderate AD, reported significant improvements on multiple measures of cognition [58,59]. Further research is required to verify whether supplementation of ketone bodies is an effective therapeutic approach for AD.…”

Section: Current Strategies Targeting Mitochondria and Bioenergetics mentioning

confidence: 99%

Targeting the Prodromal Stage of Alzheimer's Disease: Bioenergetic and Mitochondrial Opportunities

2015

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Alzheimer's disease (AD) has a complex and progressive neurodegenerative phenotype, with hypometabolism and impaired mitochondrial bioenergetics among the earliest pathogenic events. Bioenergetic deficits are well documented in preclinical models of mammalian aging and AD, emerge early in the prodromal phase of AD, and in those at risk for AD. This review discusses the importance of early therapeutic intervention during the prodromal stage that precedes irreversible degeneration in AD. Mechanisms of action for current mitochondrial and bioenergetic therapeutics for AD broadly fall into the following categories: 1) glucose metabolism and substrate supply; 2) mitochondrial enhancers to potentiate energy production; 3) antioxidants to scavenge reactive oxygen species and reduce oxidative damage; 4) candidates that target apoptotic and mitophagy pathways to either remove damaged mitochondria or prevent neuronal death. Thus far, mitochondrial therapeutic strategies have shown promise at the preclinical stage but have had little-to-no success in clinical trials. Lessons learned from preclinical and clinical therapeutic studies are discussed. Understanding the bioenergetic adaptations that occur during aging and AD led us to focus on a systems biology approach that targets the bioenergetic system rather than a single component of this system. Bioenergetic system-level therapeutics personalized to bioenergetic phenotype would target bioenergetic deficits across the prodromal and clinical stages to prevent and delay progression of AD.

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