Maternal Family History of Alzheimer’s Disease Predisposes to Reduced Brain Glucose Metabolism

Department of Psychiatry, New York University School of Medicine, 560 First Avenue, New York, NY 10016, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 11/2007; 104(48):19067-72. DOI: 10.1073/pnas.0705036104
Source: PubMed


Having a parent affected with late-onset Alzheimer's disease (AD) is a risk factor for developing AD among cognitively normal subjects. We examined whether cognitively normal subjects with a parental family history of AD show cerebral metabolic rate of glucose (CMRglc) reductions consistent with AD as compared with those without a family history and whether there are parent gender effects. Forty-nine 50- to 80-year-old normal subjects were examined who received clinical, neuropsychological, and 2-[(18)F]fluoro-2-deoxy-d-glucose-positron emission tomography examinations, including 16 subjects with a maternal (FHm) and eight with a paternal (FHp) family history of AD and 25 with no family history (FH(-)). FH groups were comparable for demographic and neuropsychological measures. As compared with both FH(-) and FHp groups, FHm subjects showed CMRglc reductions in the same regions as clinically affected AD patients, involving the posterior cingulate cortex/precuneus, parietotemporal and frontal cortices, and medial temporal lobes (P < 0.05, corrected for multiple comparisons). These effects remained significant after accounting for possible risk factors for AD, including age, gender, education, apolipoprotein E genotype, and subjective memory complaints. No CMRglc differences were found between FHp and FH(-) subjects. This study shows a relationship between reduced CMRglc in AD-vulnerable brain regions and a maternal family history of AD in cognitively normal individuals.

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Available from: Miroslaw Brys, Jan 29, 2015
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    • "Similarly, La Rue et al. (2008) showed that family history was associated with subtle differences in serial recall curves such that individuals with a family history of AD tended to recall more recently presented words (i.e., exhibited a greater recency effect) compared with no history controls, despite having recalled an equal number of items overall. Other studies have found little evidence for family history effects on baseline assessments of standard neuropsychological measures (e.g., Donix et al., 2010; Hayden et al., 2009; Johnson et al., 2006; Mosconi et al., 2007; Okonkwo et al., 2012). It should be noted that one study has shown relatively widespread family history differences on composite measures of processing speed, memory and executive functioning after controlling for APOE genotype (Donix et al., 2012). "
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    ABSTRACT: A family history of Alzheimer's disease (AD) increases the risk of developing AD and can influence the accumulation of well-established AD biomarkers. There is some evidence that family history can influence episodic memory performance even in cognitively normal individuals. We attempted to replicate the effect of family history on episodic memory and used a specific computational model of binary decision making (the diffusion model) to understand precisely how family history influences cognition. Finally, we assessed the sensitivity of model parameters to family history controlling for standard neuropsychological test performance. Across 2 experiments, cognitively healthy participants from the Adult Children Study completed an episodic recognition test consisting of high- and low-frequency words. The diffusion model was applied to decompose accuracy and reaction time (RT) into latent parameters which were analyzed as a function of family history. In both experiments, individuals with a family history of AD exhibited lower recognition accuracy and this occurred in the absence of an apolipoprotein E (APOE) ε4 allele. The diffusion model revealed this difference was due to changes in the quality of information accumulation (the drift rate) and not differences in response caution or other model parameters. This difference remained after controlling for several standard neuropsychological tests. These results confirm that the presence of a family history of AD confers a subtle cognitive deficit in episodic memory as reflected by decreased drift rate that cannot be attributed to APOE. This measure may serve as a novel cognitive marker of preclinical AD. (PsycINFO Database Record (c) 2015 APA, all rights reserved).
    Neuropsychology 07/2015; DOI:10.1037/neu0000222 · 3.27 Impact Factor
    • "Consistent with this, reduced glucose metabolism can be demonstrated not only in ApoE4 carriers but also in other persons at risk for developing Alzheimer's disease decades before the onset of the disease (Mosconi et al. 2008). As mitochondrial DNA is maternally inherited in humans, it is interesting that brain glucose metabolism is lower in elderly with a maternal family history of Alzheimer's disease than in those with a paternal family history and in controls with a negative family history of Alzheimer's disease (Mosconi et al. 2007). Furthermore, in cognitively normal persons between 32 and 72 years of age with a family history of Alzheimer's disease, brain glucose metabolism is lowest in those where both parents had suffered from the disease, intermediate in those with a maternal history of the disorder and highest in those with a paternal family history (Mosconi et al. 2014). "
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    ABSTRACT: Diet supplementation with ketone bodies (acetoacetate and β-hydroxybuturate) or medium-length fatty acids generating ketone bodies has consistently been found to cause modest improvement of mental function in Alzheimer's patients. It was suggested that the therapeutic effect might be more pronounced if treatment was begun at a preclinical stage of the disease instead of well after its manifestation. The preclinical stage is characterized by decade-long glucose hypometabolism in brain, but ketone body metabolism is intact even initially after disease manifestation. One reason for the impaired glucose metabolism may be early destruction of the noradrenergic brain stem nucleus, locus coeruleus, which stimulates glucose metabolism, at least in astrocytes. These glial cells are essential in Alzheimer pathogenesis. The β-amyloid peptide Aβ interferes with their cholinergic innervation, which impairs synaptic function due to diminished astrocytic glutamate release. Aβ also reduces glucose metabolism and causes hyperexcitability. Ketone bodies are similarly used against seizures, but the effectively used concentrations are so high that they must interfere with glucose metabolism and de-novo synthesis of neurotransmitter glutamate, reducing neuronal glutamatergic signaling. The lower ketone body concentrations used in Alzheimer's disease may owe their effect to support of energy metabolism, but might also inhibit release of gliotransmitter glutamate. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    Journal of Neurochemistry 04/2015; 134(1). DOI:10.1111/jnc.13107 · 4.28 Impact Factor
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    • "Indeed, unknown genegene and gene-environment interactions are likely to modulate the effect of this genetic factor on brain structure and function, potentially resulting in both overestimation and masking of APOE4 effects (see Donix et al. 2012 for review). In this respect, APOE genotype and family history risk were shown to have independent and/or additive contributions to brain structure (Donix et al. 2010b; Honea et al. 2010, 2011) or metabolism (Mosconi et al. 2007, 2009). "
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    ABSTRACT: The ε4 allele of the apolipoprotein E (APOE4) is associated with an increased risk of developing Alzheimer's disease (AD). Hence, several studies have compared the brain characteristics of APOE4 carriers versus non-carriers in presymptomatic stages to determine early AD biomarkers. The present review provides an overview on APOE4-related brain changes in cognitively normal individuals, focusing on the main neuroimaging biomarkers for AD, i.e. cortical beta-amyloid (Aβ) deposition, hypometabolism and atrophy. The most consistent findings are observed with Aβ deposition as most studies report significantly higher cortical Aβ load in APOE4 carriers compared with non-carriers. Fluorodeoxyglucose-positron emission tomography studies are rare and tend to show hypometabolism in brain regions typically impaired in AD. Structural magnetic resonance imaging findings are the most numerous and also the most discrepant, showing atrophy in AD-sensitive regions in some studies but contradicting results as well. Altogether, this suggests a graded effect of APOE4, with a predominant effect on Aβ over brain structure and metabolism. Multimodal studies confirm this view and also suggest that APOE4 effects on brain structure and function are mediated by both Aβ-dependent and Aβ-independent pathological processes. Neuroimaging studies on asymptomatic APOE4 carriers offer relevant information to the understanding of early pathological mechanisms of the disease, although caution is needed as to whether APOE4 effects reflect AD pathological processes, and are representative of these effects in non-carriers.
    Neuropsychology Review 08/2014; 24(3). DOI:10.1007/s11065-014-9263-8 · 4.59 Impact Factor
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