Article

Functional magnetic resonance imaging and magnetoencephalography differences associated with APOEε4 in young healthy adults

Geriatric Psychiatry Branch, National Institute of Mental Health, Bethesda, Maryland, USA.
Neuroreport (Impact Factor: 1.52). 11/2006; 17(15):1585-90. DOI: 10.1097/01.wnr.0000234745.27571.d1
Source: PubMed

ABSTRACT

Functional neural alterations are present in middle-aged to late-aged healthy individuals carrying the epsilon4 allele of the apolipoprotein E (APOEepsilon4) gene, a known risk factor for Alzheimer's disease. Neural activity was measured in young adults with and without the epsilon4 allele (APOEepsilon4+ and APOEepsilon4-) by functional magnetic resonance imaging and magnetoencephalography while performing a visual working memory task on two separate days. Greater activity was observed in frontal areas and cingulate gyri in APOEepsilon4+ participants by both functional magnetic resonance imaging and magnetoencephalography with regional blood oxygenation level-dependent responses correlating with increased theta band power. The findings suggest that the presence of the APOEepsilon4 allele has physiological consequences before aging that may contribute to risk for Alzheimer's disease.

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    • "Furthermore, decreases in cerebral glucose metabolism are a known biomarker for AD [139], and cognitively-normal, middle-aged APOE ε4 carriers have AD-like changes in cerebral glucose metabolism [140] [141], with a possible gene-dose effect [142]. A handful of studies using functional magnetic resonance imaging of the default mode network (DMN) have also shown differential oxygen uptake in the brain at rest in young APOE ε4 carriers, indicating differences in brain metabolic function early in life [143] [144] [145]. Some have argued that default mode network changes may more closely represent actual brain oxygen consumption [146] [147] and thus mitochondrial function. "
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    ABSTRACT: Although Alzheimer's Disease (AD) is the most common neurodegenerative disease, the etiology of AD is not well understood. In some cases, genetic factors explain AD risk, but a high percentage of late-onset AD is unexplained. The fact that AD is associated with a number of physical and systemic manifestations suggests that AD is a multifactorial disease that affects both the CNS and periphery. Interestingly, a common feature of many systemic processes linked to AD is involvement in energy metabolism. The goals of this review are to 1) explore the evidence that peripheral processes contribute to AD risk, 2) explore ways that AD modulates whole-body changes, and 3) discuss the role of genetics, mitochondria, and vascular mechanisms as underlying factors that could mediate both central and peripheral manifestations of AD. Despite efforts to strictly define AD as a homogeneous CNS disease, there may be no single etiologic pathway leading to the syndrome of AD dementia. Rather, the neurodegenerative process may involve some degree of baseline genetic risk that is modified by external risk factors. Continued research into the diverse but related processes linked to AD risk is necessary for successful development of disease -modifying therapies.
    Full-text · Article · Apr 2014 · Biochimica et Biophysica Acta
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    • "Furthermore, decreases in cerebral glucose metabolism are a known biomarker for AD [139], and cognitively-normal, middle-aged APOE ε4 carriers have AD-like changes in cerebral glucose metabolism [140] [141], with a possible gene-dose effect [142]. A handful of studies using functional magnetic resonance imaging of the default mode network (DMN) have also shown differential oxygen uptake in the brain at rest in young APOE ε4 carriers, indicating differences in brain metabolic function early in life [143] [144] [145]. Some have argued that default mode network changes may more closely represent actual brain oxygen consumption [146] [147] and thus mitochondrial function. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Although Alzheimer’s Disease (AD) is the most common neurodegenerative disease, the etiology of AD is not well understood. In some cases, genetic factors explain AD risk, but a high percentage of late-onset AD is unexplained. The fact that AD is associated with a number of physical and systemic manifestations suggests that AD is a multifactorial disease that affects both the CNS and periphery. Interestingly, a common feature of many systemic processes linked to AD is involvement in energy metabolism. The goals of this review are to 1) explore the evidence that peripheral processes contribute to AD risk, 2) explore ways that AD modulates whole-body changes, and 3) discuss the role of genetics, mitochondria, and vascular mechanisms as underlying factors that could mediate both central and peripheral manifestations of AD. Despite efforts to strictly define AD as a homogeneous CNS disease, there may be no single etiologic pathway leading to the syndrome of AD dementia. Rather, the neurodegenerative process may involve some degree of baseline genetic risk that is modified by external risk factors. Continued research into the diverse but related processes linked to AD risk is necessary for successful development of disease –modifying therapies.
    Full-text · Article · Jan 2014 · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease
    • "). Recently, neuroimaging studies have looked into the effect of apoE with the focus mostly on E4 with inconclusive results (Filbey et al. 2006; Trachtenberg et al. 2012a, b; Deeny et al. 2008). A different issue concerns the assessment of dynamic brain function and the possible effects of apoE on this function . "
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    ABSTRACT: Conference abstract for the International Neuroinformatics Coordinating Facility (INCF) Neuroinformatics Conference, Stockholm, Sweden. In this study, we analyzed the effect of apolipoprotein E (apoE) genotype on SNI distributions in cognitively healthy subjects of various ages to determine the relations between apoE genotype and neural communication. ApoE is involved in lipid metabolism in the brain but its effects on brain function are not understood. Three apoE isoforms (E4, E3, and E2) are the result of cysteine-arginine interchanges at two sites: there are zero interchanges in E4, one interchange in E3, and two interchanges in E2. The resulting six apoE genotypes yield five groups with respect to the number of cysteine residues per mole (0-4 CysR/mole). The use of the number of CysR/mole to characterize the apoE molecule converts the categorical apoE genotype scale, consisting of 6 distinct genotypes above, to a 5-point continuous scale, allowing the use of statistical analyses suitable for continuous variables. Using such analyses, here we show for the first time that apoE affects in a graded and orderly manner neural communication, as assessed by analyzing the relation between the number of CysR/mole and synchronous neural interactions (SNI) measured by magnetoencephalography (MEG) in 130 cognitively healthy subjects. By investigating the statistical properties along the range of CysR/mole SNI distributions, the 4-CysR/mole (E2/2) SNI distribution was found to have unique properties. The special status of the 4-CysR/mole distribution was reinforced by the results of a hierarchical tree analysis (see figure) where the 4-CysR/mole (E2/2) SNI distribution occupied a separate division by itself and the remaining CysR/mole SNI distributions were placed at increasing distances from the 4-CysR/mole distribution, according to their number of CysR/mole, with the 0-CysR/mole (E4/4) being farthest away. These results support the idea that the number of CysR/mole is an important quantitative factor underlying the effect of apoE on SNI. In addition, these findings suggest that the 4-CysR/mole (E2/2) SNI distribution could serve as a reference distribution. When the SNI distributions of individual subjects were expressed as distances from this reference distribution, there was a substantial overlap among subjects of various CysR/mole. This orderly variation of SNI with the number of CysR/mole is in keeping with recent advances and ideas regarding the molecular mechanisms underlying the differential effects of apoE in the brain which emphasize (a) the healthier stability conferred on the apoE molecule by the increasing number of cysteine-arginine interchanges, with 4-CysR/mole (E2/2) being the best case, as opposed to (b) the instability and increased chance of toxic fragmentation of the apoE molecule with lower number of CysR/mole, with 0-CysR/mole (E4/4) as the worst case. Overall, we show for the first time that the apoE genotype affected the SNI distribution in a systematic and graded fashion, according to the number of CysR/mole in the apoE molecule.
    No preview · Article · Jan 2013 · Frontiers in Neuroinformatics
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