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Cited by 162Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchDiet and metabolism studies

Hypometabolism as a therapeutic target in Alzheimer's disease

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Costantini, Lauren C, Barr, Linda J, Vogel, Janet L, Henderson, Samuel T·2008·BMC Neuroscience
DOI 10.1186/1471-2202-9-s2-s16PMC PMC2604900
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Abstract

The pathology of Alzheimer's disease (AD) is characterized by cerebral atrophy in frontal, temporal, and parietal regions, with senile plaques, dystrophic neurites, and neurofibrillar tangles within defined areas of the brain. Another characteristic of AD is regional hypometabolism in the brain. This decline in cerebral glucose metabolism occurs before pathology and symptoms manifest, continues as symptoms progress, and is more severe than that of normal aging. Ketone bodies are an efficient alternative fuel for cells that are unable to metabolize glucose or are 'starved' of glucose. AC-1202 is designed to elevate serum ketone levels safely. We previously showed that treatment with AC-1202 in patients with mild-to-moderate AD improves memory and cognition. Treatment outcomes were influenced by apolipoprotein E genotype status. These data suggest that AC-1202 may be an effective treatment for cognitive dysfunction by providing an alternative substrate for use by glucose-compromised neurons.

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  • Clinical studies have shown that treatment with a ketogenic agent improved cognitive performance in AD patients, but the therapeutic benefits appeared to be confined to ApoE4 noncarriers.

    “Although clinical studies have shown that treatment with a ketogenic agent improved cognitive performance in AD patients, the therapeutic benefits appeared to be confined to ApoE4 noncarriers (Reger et al., 2004;Costantini et al., 2008;Henderson et al., 2009).”

    From Human ApoE Isoforms Differentially Modulate Brain Glucose and Ketone Body Metabolism: Implications for Alzheimer's Disease Risk Reduction and Early Intervention (2018) · cites this paper as Costantini et al., 2008

    The Results section (‘AC-1202 in patients with cognitive impairments’) reports improved cognition in AD trials, with benefits most apparent in ApoE4-negative patients. The Conclusion says the effects were more marked in that subgroup, but does not say benefits were confined to noncarriers. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • Individuals with ApoE4 may be deficient in the transporters that control cellular uptake of ketone bodies or/and mitochondrial enzymes that convert ketone bodies to their metabolites.

    “Several clinical studies reported that ApoE4 carriers did not benefit from a ketogenic agent (Reger et al., 2004;Costantini et al., 2008), suggesting that individuals with ApoE4 may be deficient in the transporters that control the cellular uptake of ketone bodies or/and mitochondrial enzymes that convert the ketone bodies to their metabolites.”

    From Human ApoE Isoforms Differentially Modulate Brain Glucose and Ketone Body Metabolism: Implications for Alzheimer's Disease Risk Reduction and Early Intervention (2018) · cites this paper as Costantini et al., 2008

    The Results (AC-1202 in patients with cognitive impairments; page unavailable) report greater cognitive improvement in ApoE4-negative than ApoE4-positive patients, and the Conclusion says AC-1202’s effects were more marked in the ApoE4-negative subgroup. The paper does not suggest that ApoE4 carriers are deficient in ketone-uptake transporters or mitochondrial enzymes; it offers differing dose responses, pathophysiology, or disease stage as possible explanations. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

  • Several clinical studies reported that ApoE4 carriers did not benefit from a ketogenic agent.

    “Several clinical studies reported that ApoE4 carriers did not benefit from a ketogenic agent (Reger et al., 2004;Costantini et al., 2008), suggesting that individuals with ApoE4 may be deficient in the transporters that control the cellular uptake of ketone bodies or/and mitochondrial enzymes that convert the ketone bodies to their metabolites.”

    From Human ApoE Isoforms Differentially Modulate Brain Glucose and Ketone Body Metabolism: Implications for Alzheimer's Disease Risk Reduction and Early Intervention (2018) · cites this paper as Costantini et al., 2008

    The Results section (AC-1202 in patients with cognitive impairments; page unavailable) describes three clinical trials and reports stronger responses in ApoE4-negative patients. The Conclusion likewise says AC-1202’s effects were more marked in that subgroup. Neither passage establishes that ApoE4 carriers received no benefit from the ketogenic agent. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

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Cited by

Sorted by citations

Authors
Costantini, L. C., Barr, L. J., Vogel, J. L., & Henderson, S. T.
Corresponding author
Costantini, Lauren C
Venue
BMC Neuroscience
Publisher
Springer Science and Business Media LLC
Published
2008-12
Volume
9
Issue
S2
Pages
S16-S16
ISSN
1471-2202 (ISSN-L)
DOI
10.1186/1471-2202-9-s2-s16
PMC
PMC2604900
OpenAlex
W2021779846
Cited by
162
References
7
Citations by year
2026: 5 · 2025: 16 · 2024: 13 · 2023: 10 · 2022: 12 · 2021: 11 · 2020: 9 · 2019: 13 · 2018: 8 · 2017: 16 · 2016: 12 · 2015: 6 · 2014: 6 · 2013: 5 · 2012: 4
FWCI
0.59
Type
journal article
Language
en
Open access
Licence
Locations
  • BMC Neuroscience (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
  • Health Sciences › Medicine › Physiology › Diet and metabolism studies
Keywords
Alzheimer's disease, brain hypometabolism, ketone bodies, ketone supplementation, brain glucose metabolism, APOE genotype, cognitive impairment, memory impairment
MeSH terms
Alzheimer Disease, Animals, Apolipoproteins E, Brain, Cognition, Glucose, Humans, Ketone Bodies, Memory, Triglycerides

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