Dissecting the Gene Dose-Effects of the APOE ε4 and ε2 Alleles on Hippocampal Volumes in Aging and Alzheimer’s Disease

Hostage, Christopher A.; Choudhury, Kingshuk Roy; Doraiswamy, P. Murali; Petrella, Jeffrey R.

doi:10.1371/journal.pone.0054483

Cited by 70 publications

(60 citation statements)

References 43 publications

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“…ApoE has numerous roles in behavioral and cognitive functions, including regulation of anxiety and cognitive performance during normal aging and in the context of neurodegenerative disease (Raber et al, 2003;Raber, 2007;Verghese et al, 2011). Several neurobiological functions associated with PTSD have been shown to be modulated by apoE isoform, including hippocampal volume (Hostage et al, 2013), cognitive impairment (Caselli et al, 2007), and neuroendocrine alterations related to the HPA axis (Gil-Bea et al, 2010;Peskind et al, 2001;Raber et al, 2000).…”

Section: Introductionmentioning

confidence: 99%

ApoE2 Exaggerates PTSD-Related Behavioral, Cognitive, and Neuroendocrine Alterations

Johnson

Zuloaga

Bidiman

et al. 2015

Neuropsychopharmacol

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Apolipoprotein E (apoE) is an essential component of lipoprotein particles in both the brain and periphery, and exists in three isoforms in the human population: E2, E3, and E4. ApoE has numerous, well-established roles in neurobiology. Most notably, E4 is associated with earlier onset and increased risk of Alzheimer's disease (AD). Although possession of E2 is protective in the context of AD, E2 appears to confer an increased incidence and severity of posttraumatic stress disorder (PTSD). However, the biological processes underlying this link remain unclear. In this study, we began to elucidate these associations by examining the effects of apoE on PTSD severity in combat veterans, and on PTSD-like behavior in mice with human apoE. In a group of 92 veterans with PTSD, we observed significantly higher Clinician-Administered PTSD Scale and PTSD Checklist scores in E2+ individuals, as well as alterations in salivary cortisol levels. Furthermore, we measured behavioral and biological outcomes in mice expressing human apoE after a single stressful event as well as following a period of chronic variable stress, a model of combat-related trauma. Mice with E2 showed impairments in fear extinction, and behavioral, cognitive, and neuroendocrine alterations following trauma. To the best of our knowledge, these data constitute the first translational demonstration of PTSD severity in men and PTSD-like symptoms in mice with E2, and point to apoE as a novel biomarker of susceptibility, and potential therapeutic target, for PTSD.

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Section: Introductionmentioning

confidence: 99%

ApoE2 Exaggerates PTSD-Related Behavioral, Cognitive, and Neuroendocrine Alterations

Johnson

Zuloaga

Bidiman

et al. 2015

Neuropsychopharmacol

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“…APOE 4+ CTLs have greater detectable brain amyloid (44) and lower CSF Aβ (52; 53) than APOE 4 non-carriers. Although APOE 4+ controls do not typically have lower baseline whole hippocampal volume than APOE 4- controls (54-56), APOE 4 is associated with differences in hippocampal subfield structure (55; 57) and hippocampal atrophy rates (58) in healthy adults. It is possible that part of the apparent relationship between CSF Aβ and baseline hippocampal volume in non-demented adults was diminished after controlling for that allele.…”

Section: Relationships Of Structural Mri To Other Ad Biomarkersmentioning

confidence: 96%

A Focus on Structural Brain Imaging in the Alzheimer’s Disease Neuroimaging Initiative

Braskie¹,

Thompson²

2014

Biological Psychiatry

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In recent years, there has been a wealth of laboratories and consortia that use neuroimaging to evaluate the risk for and progression of Alzheimer's disease (AD). One such consortium is the Alzheimer's Disease Neuroimaging Initiative (ADNI) - a longitudinal, multi-center study that evaluates a range of biomarkers for use in AD diagnoses, predicting patient outcomes, and for clinical trials. These biomarkers include brain metrics derived from magnetic resonance imaging (MRI) and positron emission tomography (PET) scans, and metrics derived from blood and cerebrospinal fluid (CSF). Here we focus on ADNI studies, published between 2011 and March 2013, for which structural MRI was a major outcome measure. Our main goal here was to review key papers offering insights into AD progression, and the relationships of structural MRI measures to cognition and to other biomarkers in AD. In the Supplemental Materials, we also discuss genetic and environmental risk factors for AD, and exciting new analysis tools for the efficient evaluation of large scale structural MRI data sets such as ADNI.

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“…Other regions are also reported such as the lateral temporal and prefrontal cortex (Wishart et al, 2006) or parietal areas (Honea et al, 2009). Yet, there have also been numerous studies reporting no significant differences between APOE4 carriers and non carriers in terms of brain volume or cortical thickness (Soininen et al, 1995;Schmidt et al, 1996;Reiman et al, 1998;Jack et al, 1998;Cohen et al, 2001;Han et al, 2007;Schuff et al, 2009;Filippini et al, 2009Filippini et al, , 2011Dennis et al, 2010;Kukolja et al, 2010;Liu et al, 2010a;Westlye et al, 2011;Bunce et al, 2012;Protas et al, 2013;Hostage et al, 2013) or even showing greater volume (Honea et al, 2009) or cortical thickness (Espeseth et al, 2008) in APOE4 carriers compared to non carriers. Some studies suggest that the effect of APOE4 is more marked in young that in elderly individuals (Lind et al, 2006;Wishart et al, 2006), but the reverse has also been reported (Mueller et al, 2008;Mueller and Weiner 2009).…”

Section: Apoe4 and Structural Mri / Atrophymentioning

confidence: 99%

Neuroimaging biomarkers for Alzheimer's disease in asymptomatic APOE4 carriers

Chételat

Fouquet

2013

Revue Neurologique

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Abstract:Introduction. The E4 allele of the apolipoprotein E (APOE4) is the major known genetic risk factor for AD, with a dramatic increase in the risk of developing AD as the number of APOE4 alleles increases from 0 to 2. For this reason, asymptomatic APOE4 carriers as a group offer a great opportunity to seek for the presence of early biomarkers for AD. The present article reviews neuroimaging studies on APOE4 carriers, focusing on cognitively normal individuals and on the main neuroimaging biomarkers for AD, i.e. atrophy with structural MRI, hypometabolism with FDG-PET, and amyloid deposition with amyloid-PET imaging.State of art. There is a great number of studies on the effect of APOE4 on brain structures, and they tend to show significant atrophy in APOE4 carriers compared to non carriers especially in regions susceptible to AD pathology such as the hippocampus. However, results are rather discrepant which suggests that the effect of APOE4 on brain structure is subtle. As for FDG-PET metabolism, the few studies show decreased metabolism, again especially in AD-sensitive regions such as posterior associative parietal areas, with a dose-dependent effect (i.e. worsening as the number of APOE4 alleles increases). Finally, there is a unanimous and major effect of APOE4 on amyloid deposition with an increase in Aβ load as the number of APOE4 alleles increases and a decrease in the age of predicted amyloid-positivity in APOE4 carriers. This graded effect of APOE4 on atrophy, hypometabolism, and amyloid deposition is consistent with multimodal neuroimaging studies suggestive of a predominant effect of APOE4 on amyloid rather than tau-related injury and on brain metabolism rather than brain structure. Neuroimaging studies also suggest that APOE4 effects may be mediated by both Aβ-dependent and Aβ-independent pathological processes. This contradicts the view that Aβ pathology is a necessary upstream event to neuronal injury in AD. Perspectives and conclusion. Future studies would tell whether the mechanisms and sequences evidenced in carriers is comparable to those found in non carriers, but it is likely that APOE4 not only influences the risk for AD, but also modulates the physiopathological cascade. Altogether, APOE4 carriers offer a great opportunity to investigate brain changes in the asymptomatic stages of AD and to further our understanding of the physiopathology of the disease, although precaution is needed for interpretation in AD at large. Etat des connaissances. De très nombreuses études ont évalué les effets de l'APOE4 sur la structure cérébrale. Les résultats sont très divergents, même s'ils suggèrent dans l'ensemble un effet subtile dans le sens d'une diminution de volume dans les régions les plus sensibles à la MA telles que l'hippocampe. Les rares études en TEP-FDG indiquent une baisse du métabolisme là encore dans les régions altérées précocement dans la MA comme le cortex associatif pariétal postérieur, avec un effet dose-dépendant (i.e. fonction du nombre d'allèles APOE4). Enfin, l'effet sur les d...

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Dissecting the Gene Dose-Effects of the APOE ε4 and ε2 Alleles on Hippocampal Volumes in Aging and Alzheimer’s Disease

Cited by 70 publications

References 43 publications

ApoE2 Exaggerates PTSD-Related Behavioral, Cognitive, and Neuroendocrine Alterations

ApoE2 Exaggerates PTSD-Related Behavioral, Cognitive, and Neuroendocrine Alterations

A Focus on Structural Brain Imaging in the Alzheimer’s Disease Neuroimaging Initiative

Neuroimaging biomarkers for Alzheimer's disease in asymptomatic APOE4 carriers

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