Brain metabolic decreases related to the dose of the ApoE e4 allele in Alzheimer's disease

Mosconi, Lisa; Nacmias, Benedetta; Sorbi, Sandro; Cristofaro, Maria Teresa De; Fayazz, M.; Tedde, Andrea; Bracco, Laura; Herholz, Karl; Pupi, Alberto

doi:10.1136/jnnp.2003.014993

Cited by 83 publications

(56 citation statements)

References 35 publications

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“…E4(ϩ) subjects may have more global declines in CMRglc, as low rates were detected in other areas of the brain not seen in E4(Ϫ) subjects. 18 Thus, some differences may exist between E4 carriers in other regions of the brain or in progression of the CMRglc decline. 19 The molecular cause of the hypometabolism remains unclear.…”

Section: Glucose Metabolism In Admentioning

confidence: 99%

Ketone Bodies as a Therapeutic for Alzheimer's Disease

Henderson¹

2008

Neurotherapeutics

301

120

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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: Glucose Metabolism In Admentioning

confidence: 99%

Ketone Bodies as a Therapeutic for Alzheimer's Disease

Henderson¹

2008

Neurotherapeutics

301

120

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“…As previously described, 20 all subjects underwent clinical and neuropsychological examinations to exclude organic brain disease and cognitive impairment.…”

Section: Controlsmentioning

confidence: 99%

Metabolic interaction between ApoE genotype and onset age in Alzheimer's disease: implications for brain reserve

Mosconi¹,

Herholz

Prohovnik³

et al. 2005

Journal of Neurology, Neurosurgery & Psychiatry

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Background: Clinically apparent Alzheimer's disease (AD) is thought to result when brain tissue damage exceeds a critical threshold of ''brain reserve'', a process possibly accelerated by the apolipoprotein E (ApoE) E4 allele. The interaction between onset age and ApoE genotype was investigated to assess whether early disease onset (,65 years) in patients carrying the E4 allele is associated with greater cerebral metabolic (regional cerebral metabolic rate of glucose utilisation, rCMRgl) reduction. Methods: AD patients, divided into early (EOAD; 27 patients) and late onset (LOAD; 65 patients) groups, both groups balanced as to the number of E4 carriers (E4+) and non-carriers (E42), and matched controls (NC; 35 cases) underwent 18 F-FDG PET ([ 18 F]fluorodeoxyglucose positron emission tomography) scanning. SPM'99 software was used to compare AD patients to NC and to perform a two way ANOVA with onset age and ApoE genotype as grouping factors. Results were considered significant at p,0.001, uncorrected. Results: AD patients demonstrated rCMRgl reductions compared to NC, with rCMRgl lower in association cortex and relatively higher in limbic areas in EOAD compared to LOAD subjects. rCMRgl was lower in the anterior cingulate and frontal cortex for E4+ compared to E42 subjects. A significant onset age by ApoE interaction was detected in the hippocampi and basal frontal cortex, with EOAD E4+ subjects having the greatest rCMRgl reduction. Conclusions: The interactive effects of early onset age, possibly reflecting lower brain reserve, and ApoE E4 allele, possibly leading to greater tissue damage, lead to reduced tolerance to the pathophysiological effects of AD in key brain regions.

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“…In line with the strong and consistent results for APOE when using LOAD as the phenotype, most T-1 weighted MRI studies reported an association of APOE e4 with accelerated LOAD-related volume loss in the hippocampal region. [53][54][55][56] This is supported by several studies exploring the effect of the APOE e4 allele on glucose metabolism using FDG-PET, [57][58][59][60] or amyloid deposition using ([¹¹C] PiB-PET. [61][62][63] Few studies have examined the association between other genes and LOAD imaging measures, and most of these were GWAS studies.…”

Section: Genetic Variation and Neuroimaging Measures In Loadmentioning

confidence: 74%