Reduced Hippocampal Volume in Healthy Young ApoE4 Carriers: An MRI Study

O’Dwyer, Laurence; Lamberton, Franck; Matura, Silke; Tanner, Colby J.; Scheibe, Monika; Miller, Julia; Rujescu, Dan; Prvulovic, David; Hampel, Harald

doi:10.1371/journal.pone.0048895

Cited by 177 publications

(116 citation statements)

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“…Nominally significant associations of an APOE risk variant with HV (P=0.0054) and a CD33 variant with ICV (P=0.0058) were observed. Since the mid 1990's (Supplementary Table 5) some studies have described significant associations between the APOE-ε4 allele and smaller HV (den Heijer, et al, 2002, Lehtovirta, et al, 1995, Lehtovirta, et al, 1996, Lind, et al, 2006, Liu, et al, 2014, Lu, et al, 2011, Morra, et al, 2009, O'Dwyer, et al, 2012, Plassman, et al, 1997, however other studies did not find such an association (Ferencz, et al, 2013, Reiman, et al, 1998, Schmidt, et al, 1996. Using the largest sample size to date (N=11,550), as previously reported by our group, our findings are supportive of an association of the APOE-ε4 locus with smaller HV .…”

Section: Discussionsupporting

confidence: 85%

O4‐04‐05: Association of Alzheimer Disease Gwas Loci With Mri‐markers of Brain Aging

Chauhan

Adams

Bis

et al. 2014

Alzheimer's & Dementia

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Whether novel risk variants of Alzheimer's disease (AD) identified through genome-wide association studies (GWAS) also influence MRI-based intermediate phenotypes of AD in the general population is unclear. We studied association of 24 AD risk loci with intracranial volume (ICV), total brain volume (TBV), hippocampal volume (HV), white matter hyperintensity (WMH) burden, and brain infarcts in a meta-analysis of genetic association studies from large populationbased samples (N=8,175-11,550). In single-SNP based tests, AD risk allele of APOE (rs2075650) was associated with smaller HV (p=0.0054) and CD33 (rs3865444) with smaller ICV (p=0.0058) In gene-based tests, there was associations of HLA-DRB1 with TBV (p=0.0006) and BIN1 with HV (p=0.00089). A weighted AD genetic risk score was associated with smaller HV (beta±SE= −0.047±0.013, p=0.00041), even after excluding the APOE locus (p=0.029). However, only association of AD genetic risk score with HV, including APOE, was significant after multiple testing correction (including number of independent phenotypes tested). These results suggest that novel AD genetic risk variants may contribute to structural brain aging in non-demented older community persons.

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Section: Discussionsupporting

confidence: 85%

O4‐04‐05: Association of Alzheimer Disease Gwas Loci With Mri‐markers of Brain Aging

Chauhan

Adams

Bis

et al. 2014

Alzheimer's & Dementia

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“…31 MCI patients were further dichotomized as APOE "4 carriers (APOE "3/"4 and APOE "4/"4) or non-carriers (APOE "3/"3).…”

Section: Genotypingmentioning

confidence: 99%

Divergent regional patterns of cerebral hypoperfusion and gray matter atrophy in mild cognitive impairment patients

Wirth

Binette

Brunecker

et al. 2016

J Cereb Blood Flow Metab

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Reductions of cerebral blood flow and gray matter structure have been implicated in early pathogenesis of Alzheimer's disease, potentially providing complementary information. The present study evaluated regional patterns of cerebral hypoperfusion and atrophy in patients with mild cognitive impairment and healthy older adults. In each participant, cerebral perfusion and gray matter structure were extracted within selected brain regions vulnerable to Alzheimer's disease using magnetic resonance imaging. Measures were compared between diagnostic groups with/without adjustment for covariates. In mild cognitive impairment patients, cerebral blood flow was significantly reduced in comparison with healthy controls in temporo-parietal regions and the basal ganglia in the absence of local gray matter atrophy. By contrast, gray matter structure was significantly reduced in the hippocampus in the absence of local hypoperfusion. Both, cerebral perfusion and gray matter structure were significantly reduced in the entorhinal and isthmus cingulate cortex in mild cognitive impairment patients compared with healthy older adults. Our results demonstrated partly divergent patterns of temporo-parietal hypoperfusion and medial-temporal atrophy in mild cognitive impairment patients, potentially indicating biomarker sensitivity to dissociable pathological mechanisms. The findings support applicability of cerebral perfusion and gray matter structure as complementary magnetic resonance imaging-based biomarkers in early Alzheimer's disease detection, a hypothesis to be further evaluated in longitudinal studies.

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“…Thus, several studies have reported a significant atrophy (or cortical thinning) in APOE4 carriers compared to non carriers, most often in brain regions most susceptible to AD, i.e. medial temporal structures (hippocampus, entorhinal cortex, etc;Plassman et al, 1997;Tohgi et al, 1997;Lemaître et al, 2005;Lind et al, 2006;Wishart et al, 2006;Burggren et al, 2008;Honea et al, 2009;Suthana et al, 2010;O'Dwyer et al, 2012). Other regions are also reported such as the lateral temporal and prefrontal cortex (Wishart et al, 2006) or parietal areas (Honea et al, 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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Reduced Hippocampal Volume in Healthy Young ApoE4 Carriers: An MRI Study

Cited by 177 publications

References 84 publications

O4‐04‐05: Association of Alzheimer Disease Gwas Loci With Mri‐markers of Brain Aging

O4‐04‐05: Association of Alzheimer Disease Gwas Loci With Mri‐markers of Brain Aging

Divergent regional patterns of cerebral hypoperfusion and gray matter atrophy in mild cognitive impairment patients

Neuroimaging biomarkers for Alzheimer's disease in asymptomatic APOE4 carriers

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