Hippocampal Volume Differences Between Healthy Young Apolipoprotein E ε2 and ε4 Carriers

Alexopoulos, Panagiotis; Richter‐Schmidinger, Tanja; Horn, Marco; Maus, Sebastian; Reichel, Martin; Sidiropoulos, Christos; Rhein, Cosima; Lewczuk, Piotr; Doerfler, Arnd; Kornhuber, Johannes

doi:10.3233/jad-2011-110356

Cited by 62 publications

(66 citation statements)

References 19 publications

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“…The current results, however, contrast with past research suggesting e2 is protective (Chiang et al, 2010;Farrer et al, 1997;Helkala et al, 1996;Lippa et al, 1997;Wilson et al, 2002). The results reported here are based on a small sample of e2 carriers, but contribute to the small number of studies that have explored e2 effects on cognition prior to older-adulthood (Alexander et al, 2007;Alexopoulos et al, 2011). Recent papers have reported differential spatial navigation strategies in e2 carriers in youth (Konishi et al, 2016), as well as altered memory function in individuals diagnosed with post-traumatic stress disorder (Freeman et al, 2005;Johnson et al, 2015;Kim et al, 2013).…”

Section: Discussioncontrasting

confidence: 54%

The APOE paradox: do attentional control differences in mid-adulthood reflect risk of late-life cognitive decline

Lancaster

Tabet

Rusted

2016

Neurobiology of Aging

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Article (Accepted Version) http://sro.sussex.ac.uk Lancaster, Claire, Tabet, Naji and Rusted, Jennifer (2016) The APOE paradox: how do attentional control differences in mid-adulthood reflect risk of late-life cognitive decline. Neurobiology of Aging, This version is available from Sussex Research Online: http://sro.sussex.ac.uk/62415/ This document is made available in accordance with publisher policies and may differ from the published version or from the version of record. If you wish to cite this item you are advised to consult the publisher's version. Please see the URL above for details on accessing the published version. Copyright and reuse:Sussex Research Online is a digital repository of the research output of the University.Copyright and all moral rights to the version of the paper presented here belong to the individual author(s) and/or other copyright owners. To the extent reasonable and practicable, the material made available in SRO has been checked for eligibility before being made available.Copies of full text items generally can be reproduced, displayed or performed and given to third parties in any format or medium for personal research or study, educational, or not-for-profit purposes without prior permission or charge, provided that the authors, title and full bibliographic details are credited, a hyperlink and/or URL is given for the original metadata page and the content is not changed in any way. AbstractPossession of an APOE e4 allele is an established risk factor for Alzheimer's disease, while the less commonly studied e2 variant is premised to offer some protection. This research explores the purported deleterious-protective dichotomy of APOE variants on attentional control in mid-adulthood. 66 volunteers, aged 45-55 years, completed three tasks that provided complementary measures of attentional control: prospective memory, sustained attention and inhibition. Performance was compared between e2 carriers, e4 carriers and e3 homozygotes (the population norm). Carriers of the e4 allele showed subtle disadvantages, compared to the e3 group, in accuracy of Stroop task and prospective memory performance. Contrary to expectations, e2 carriers showed performance disadvantages in sustained attention. The finding of detrimental effects in attentional control for both e4 and e2 complicates the current model that proposes opposing effects of these variants on later-life cognition. Future research is needed to understand how cognitive differences develop with increasing age, and the physiological mechanisms that underpin these changes.

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Section: Discussioncontrasting

confidence: 54%

The APOE paradox: do attentional control differences in mid-adulthood reflect risk of late-life cognitive decline

Lancaster

Tabet

Rusted

2016

Neurobiology of Aging

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“…APOE-ε4 carriers at birth have reduced grey matter volume in temporal areas and increased grey matter volume in frontal areas, suggesting early developmental differences in brain structure dependent on APOE genotype [65; 66]. In young healthy APOE-ε4 carriers (average age of 20–25 years), white and grey matter volumes in the medial temporal lobe (MTL) were reported to be either larger [67], unchanged [56; 68–70] or smaller [71; 72]. There are no differences, however, in the temporal cortex or hippocampus of middle-aged adults, although APOE-ε4 carriers had thinner frontal cortices, while APOE-ε2 carriers had thicker parahippocampal cortices [73; 74].…”

Section: Apoe Genotype Effects On the Normal Brainmentioning

confidence: 99%

Alzheimer's Disease Genetic Risk Factor APOE-ε4 Also Affects Normal Brain Function

Battista¹,

Heinsinger²,

Rebeck³

2016

CAR

105

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APOE-ε4 is the strongest genetic risk factor for Alzheimer’s disease (AD), and is associated with an increase in the levels of amyloid deposition and an early age of onset. Recent data demonstrate that AD pathological changes occur decades before clinical symptoms, raising questions about the precise onset of the disease. Now a convergence of approaches in mice and humans has demonstrated that APOE-ε4 affects normal brain function even very early in life in the absence of gross AD pathological changes. Normal mice expressing APOE4 have task-specific spatial learning deficits, as well as reduced NMDAR-dependent signaling and structural changes to presynaptic and postsynaptic compartments in neurons, particularly in hippocampal regions. Young humans possessing APOE-ε4 are more adept than APOE-ε4 negative individuals at some behavioral tasks, and functional magnetic resonance imaging has shown that inheritance of APOE-ε4 has specific effects on medial temporal brain activities. These findings suggest that inheritance of APOE-ε4 causes life long changes to the brain that may be related to the late risk of AD. Several possible mechanisms of how APOE-ε4 could affect brain neurochemistry, structure, and function are reviewed.

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“…ASM genotypes and ASM activity were initially analysed in 156 healthy individuals enrolled in the GENES study [45,48,49,50]. Further data were obtained from the ASPECT control group (n=133) [31].…”

Section: Methodsmentioning

confidence: 99%

Secretion of Acid Sphingomyelinase is Affected by its Polymorphic Signal Peptide

Rhein

Reichel

Mühle

et al. 2014

Cell Physiol Biochem

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Background: Acid sphingomyelinase (ASM) catalyses the hydrolysis of sphingomyelin into ceramide, which acts as a lipid messenger that regulates important cellular functions. Deregulated ASM activity has been reported for different common diseases, but the mechanisms regulating ASM activity are still debated. ASM contains an exceptional signal peptide which is polymorphic due to a variable number of a hexanucleotide sequence that determines the length of the hydrophobic core. We investigated the impact of the signal peptide polymorphism on the regulation of ASM activity and secretion in vivo and in vitro. Methods and Results: Subjects homozygous for the rare 4-repeat allele displayed significantly lower secreted ASM activity than subjects homozygous for the common 6-repeat allele. In vitro, overexpression of ASM variants encoded by 2, 8 or 9 repeats resulted in a significantly lowered ASM secretion rate. Treatment of ASM-overexpressing cells with tumour necrosis factor α induced secretion of ASM, and the secretion rate was highest for the most common ASM variant encoding 6 repeats compared to other naturally occurring variants. Conclusion: We provide evidence that the polymorphic ASM signal peptide regulates ASM secretion. It might be an evolutionary mechanism to increase ASM secretion potential, whereas an increase in lysosomal ASM activity is limited due to deleterious cellular effects.

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Hippocampal Volume Differences Between Healthy Young Apolipoprotein E ε2 and ε4 Carriers

Cited by 62 publications

References 19 publications

The APOE paradox: do attentional control differences in mid-adulthood reflect risk of late-life cognitive decline

The APOE paradox: do attentional control differences in mid-adulthood reflect risk of late-life cognitive decline

Alzheimer's Disease Genetic Risk Factor APOE-ε4 Also Affects Normal Brain Function

Secretion of Acid Sphingomyelinase is Affected by its Polymorphic Signal Peptide

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