Better Memory and Neural Efficiency in Young Apolipoprotein E  4 Carriers

Mondadori, Christian R.A.; Quervain, Dominique J.‐F. de; Buchmann, Andreas; Mustovic, Henrietta; Wollmer, M. Axel; Schmidt, Conny F.; Boesiger, Peter; Höck, Christoph; Nitsch, Roger M.; Papassotiropoulos, Andreas; Henke, Katharina

doi:10.1093/cercor/bhl103

Cited by 230 publications

(239 citation statements)

References 72 publications

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“…23,24,25 Positron emission tomography (PET) studies have consistently shown resting glucose metabolism reduction in healthy young and middleaged APOE ε4-carriers in brain regions known to be affected by AD pathology, such as the parietal, temporal and prefrontal cortices. 12,13 Taskbased functional magnetic resonance imaging (fMRI) studies have been less consistent, showing increased 11,14,15 , decreased 26,27 or even no difference 28 in task-related BOLD signal between healthy APOE ε4-carriers and non-carriers.…”

Section: Introductionmentioning

confidence: 99%

The APOE ɛ4 allele modulates brain white matter integrity in healthy adults

et al. 2010

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The Apolipoprotein E (APOE) ε4 allele is the best-established genetic risk factor for sporadic Alzheimer's disease (AD) and is also associated with structural gray matter (GM) and functional brain changes in healthy young, middle-aged and elderly subjects. Because APOE is implicated in brain mechanisms associated with white matter (WM) development and repair, we investigated the potential role played by the APOE polymorphism on WM structure in healthy younger (age range: 20-35 years) and older (aged 50-78 years) adults using diffusion tensor imaging (DTI). General reduction of fractional anisotropy (FA) and increase in mean diffusivity (MD) values was found in carriers of the APOE ε4 allele relative to non-carriers. No significant interactions between genotype and age were observed, suggesting that differences in WM structure between APOE ε4-carriers and non-carriers do not undergo significant differential changes with age. This result was not explained by differences in brain morphology or cognitive measures. The APOE ε4 allele modulates brain WM structure before any clinical or neurophysiological expression of impending disease.

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Section: Introductionmentioning

confidence: 99%

The APOE ɛ4 allele modulates brain white matter integrity in healthy adults

et al. 2010

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“…Filbey et al (18) reported greater activation in 8 APOE 4-carriers compared with 8 noncarriers in medial frontal and anterior cingulate areas using a working memory paradigm. Mondadori et al (17) reported reduced activation with an associative learning paradigm in 13 4-carriers relative to 11 2-carriers and 10 3-homozygotes. Both studies therefore suggest that the APOE genotype influences brain functions even early in adulthood.…”

mentioning

confidence: 99%

“…Thus far, reports of structural and functional effects of the APOE 4 allele in young adults are limited (17)(18)(19)(20). Only 2 small fMRI studies have tested for early life associations of the APOE polymorphism with changes in brain function.…”

mentioning

confidence: 99%

Distinct patterns of brain activity in young carriers of the APOE -ε4 allele

Filippini

MacIntosh

Hough

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

1,484

1,179

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The APOE 4 allele is a risk factor for late-life pathological changes that is also associated with anatomical and functional brain changes in middle-aged and elderly healthy subjects. We investigated structural and functional effects of the APOE polymorphism in 18 young healthy APOE 4-carriers and 18 matched noncarriers (age range: 20 -35 years). Brain activity was studied both at rest and during an encoding memory paradigm using blood oxygen level-dependent fMRI. Resting fMRI revealed increased ''default mode network'' (involving retrosplenial, medial temporal, and medial-prefrontal cortical areas) coactivation in 4-carriers relative to noncarriers. The encoding task produced greater hippocampal activation in 4-carriers relative to noncarriers. Neither result could be explained by differences in memory performance, brain morphology, or resting cerebral blood flow. The APOE 4 allele modulates brain function decades before any clinical or neurophysiological expression of neurodegenerative processes.hippocampus ͉ memory ͉ neuroimaging ͉ resting connectivity A polipoprotein E (apoE, protein; APOE, gene) is a very-lowdensity lipoprotein that removes cholesterol from the blood and carries it to the liver for processing (1). In the central nervous system, apoE has a key role in coordinating the mobilization and redistribution of cholesterol, phospholipids, and fatty acids, and it is implicated in mechanisms such as neuronal development, brain plasticity, and repair functions (2). The human APOE gene, which is encoded on chromosome 19, has 3 allelic variants ( 2, 3, and 4). The 4 allele has been associated with a higher risk of cardiovascular disease (3), both early-onset (4) and late-onset (5) Alzheimer's disease (AD), poor outcome from traumatic brain injury (6), and age-related cognitive impairment (7).Neuroimaging studies of the APOE polymorphism in healthy subjects have largely focused on gray matter (GM) alterations in middle or late life, particularly in brain regions associated with the greatest AD pathological findings. Even in asymptomatic subjects, hippocampal and frontotemporal GM reduction has been observed in APOE 4-carriers relative to noncarriers (8). Moreover, a reduction of resting glucose metabolism was reported in young and middle-aged cognitively normal APOE 4-carriers in brain regions known to be affected by AD, including the posterior cingulate, parietal, temporal, and prefrontal cortices (9-11). fMRI task-based studies (mainly investigating memory processes) have shown greater activation in middle-aged and elderly APOE 4-carriers relative to noncarriers (12-16). Although these studies suggest an influence of the APOE 4 allele on brain structure and metabolism, they do not make clear at what age these influences initially manifest. Furthermore, although differences in structure, resting metabolism, and function have each been reported in 4-carriers relative to noncarriers, it remains to be established to what extent these characteristics interact.Thus far, reports of structural and functional eff...

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“…The 354 volunteers were university students and employees/trainees recruited at the university of Zurich and via advertisements in local newspapers. The 81 subjects already participated in two functional magnetic resonance imaging studies that investigated brain activity elicited by memory tasks between different apolipoprotein E genotypes (Mondadori et al, 2007) and between different prion protein genotypes (Buchmann et al, 2008). Our sample is homogenous with respect to age, education, and memory performance.…”

Section: Subjectsmentioning

confidence: 99%

“…Education, handedness, and age showed no significant influence on morphology (tested in multiple regression analyses together with TGMV and BDNF genotype) and were therefore not modeled in both analyses. We controlled for SNPs with published influences on brain morphology such as found in the BDNF gene Hariri et al, 2003;Pezawas et al, 2004;Szeszko et al, 2005;Bueller et al, 2006) and 5-HT2a gene (Filippini et al, 2006), and for SNPs with potential influences on morphology such as found in the ApoE gene (Mondadori et al, 2007) and PrnP gene (Papassotiropoulos et al, 2005a), as well as for nonrandom genetic heterogeneity, i.e., hidden, genetic population structure (Papassotiropoulos et al, 2005b). Allelic frequencies of the SNPs with potential influences and the 5-HT2a SNP were not significantly different between the CYP46 genotypes and were not considered further.…”

Section: Statistical Analysesmentioning

confidence: 99%

A CYP46 T/C SNP modulates parahippocampal and hippocampal morphology in young subjects

Hänggi

Mondadori

Buchmann

et al. 2011

Neurobiology of Aging

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There is evidence that brain cholesterol metabolism modulates the vulnerability for Alzheimer's disease (AD). Previous data showed that brain beta-amyloid load in elderly subjects with the CYP46 (cholesterol 24S-hydroxylase) TT-positive genotype was higher than in CYP46 TT-negative elderly subjects. We investigated effects of the CYP46 T/C polymorphism on parahippocampal and hippocampal grey matter (GM) morphology in 81 young subjects using structural magnetic resonance imaging based morphometry. We found that young TT-homozygotes exhibited smallest and CC-homozygotes largest parahippocampal and hippocampal GM volumes with the volumes of the CT-heterozygotes ranging in between. Parahippocampal and hippocampal volumes were positively correlated with delayed memory performance in C-carriers and negatively with immediate memory performance in TT-homozygotes. It has been shown that the brain cholesterol metabolism in general modulates dendrite outgrowth, synaptogenesis, and neuron survival, and it was suggested that CYP46 indirectly influences beta-amyloid metabolism. CYP46 C-carriers are privileged both in terms of beta-amyloid metabolism and in terms of brain reserve due to their larger parahippocampal and hippocampal structures. The exact cellular mechanisms that translate the CYP46 allelic variation into volumetric brain differences in the parahippocampal gyrus and hippocampus are still unknown and need to be further investigated. AbstractThere is evidence that brain cholesterol metabolism modulates the vulnerability for Alzheimer's disease (AD). Previous data showed that brain -amyloid load in elderly subjects with the CYP46 (cholesterol 24S-hydroxylase) TT-positive genotype was higher than in CYP46TT-negative elderly subjects. We investigated effects of the CYP46 T/C polymorphism on parahippocampal and hippocampal grey matter (GM) morphology in 81 young subjects using structural magnetic resonance imaging based morphometry. We found that young TThomozygotes exhibited smallest and CC-homozygotes largest parahippocampal and hippocampal GM volumes with the volumes of the CT-heterozygotes ranging in between.Parahippocampal and hippocampal volumes were positively correlated with delayed memory performance in C-carriers and negatively with immediate memory performance in TThomozygotes. It has been shown that the brain cholesterol metabolism in general modulates dendrite outgrowth, synaptogenesis, and neuron survival, and it was suggested that CYP46 indirectly influences -amyloid metabolism. CYP46 C-carriers are privileged both in terms of -amyloid metabolism and in terms of brain reserve due to their larger parahippocampal and hippocampal structures. The exact cellular mechanisms that translate the CYP46 allelic variation into volumetric brain differences in the parahippocampal gyrus and hippocampus are still unknown and need to be further investigated. Keywords:Cholesterol metabolism; Single nucleotide polymorphism; CYP46 (cholesterol 24S-hydroxylase); Parahippocampal and hippocampal morphology; Alzheim...

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Better Memory and Neural Efficiency in Young Apolipoprotein E 4 Carriers

Cited by 230 publications

References 72 publications

The APOE ɛ4 allele modulates brain white matter integrity in healthy adults

The APOE ɛ4 allele modulates brain white matter integrity in healthy adults

Distinct patterns of brain activity in young carriers of the APOE -ε4 allele

A CYP46 T/C SNP modulates parahippocampal and hippocampal morphology in young subjects

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