The apolipoprotein E epsilon 4 allele is associated with ventricular expansion rate and surface morphology in dementia and normal aging

Roussotte, Florence F.; Gutman, Boris A.; Madsen, Sarah K.; Colby, John B.; Narr, Katherine L.; Thompson, Paul M.

doi:10.1016/j.neurobiolaging.2013.11.030

Cited by 28 publications

(26 citation statements)

References 61 publications

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“…Whereas studies overwhelmingly find that the APOE "4 genotype is associated with worse amyloid-b pathology, its effect on markers of neurodegeneration such as CSF tau, fludeoxyglucose PET, and structural MRI are less consistent. Studies have reported both an influence of the APOE "4 allele (Reiman et al, 1996;Galasko et al, 1998;Liu et al, 2010;Jagust et al, 2012;Hostage et al, 2013;Lehmann et al, 2013;Roussotte et al, 2014) and no effect (Soininen et al, 1995;Jack et al, 1998;Reiman et al, 1998;Sunderland et al, 2004;Drzezga et al, 2009;Fan et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

Longitudinal brain imaging in preclinical Alzheimer disease: impact of APOE ε4 genotype

Mishra

Blazey

Holtzman³

et al. 2018

Brain

119

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While prior work reliably demonstrates that the APOE ɛ4 allele has deleterious group level effects on Alzheimer disease pathology, the homogeneity of its influence across the lifespan and spatially in the brain remains unknown. Further it is unclear what combinations of factors at an individual level lead to observed group level effects of APOE genotype. To evaluate the impact of the APOE genotype on disease trajectories, we examined longitudinal MRI and PET imaging in a cohort of 497 cognitively normal middle and older aged participants. A whole-brain regional approach was used to evaluate the spatial effects of genotype on longitudinal change of amyloid-β pathology and cortical atrophy. Carriers of the ɛ4 allele had increased longitudinal accumulation of amyloid-β pathology diffusely through the cortex, but the emergence of this effect across the lifespan differed greatly by region (e.g. age 49 in precuneus, but 65 in the visual cortex) with the detrimental influence already being evident in some regions in middle age. This increased group level effect on accumulation was due to a greater proportion of ɛ4 carriers developing amyloid-β pathology, on average doing so at an earlier age, and having faster amyloid-β accumulation even after accounting for baseline amyloid-β levels. APOE ɛ4 carriers displayed faster rates of structural loss in primarily constrained to the medial temporal lobe structures at around 50 years, although this increase was modest and proportional to the elevated disease severity in APOE ɛ4 carriers. This work indicates that influence of the APOE gene on pathology can be detected starting in middle age.

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Section: Introductionmentioning

confidence: 99%

Longitudinal brain imaging in preclinical Alzheimer disease: impact of APOE ε4 genotype

Mishra

Blazey

Holtzman³

et al. 2018

Brain

119

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“…Structural neuroimaging patterns related to APOE ε4 in elderly individuals described grey matter atrophy in the medial temporal structures (Chen et al, 2007, Donix et al, 2010b, Hua et al, 2010, Risacher et al, 2010, Lu et al, 2011, Roussotte et al, 2014 such as the subiculum (Burggren et al, 2008, Suthana et al, 2010) and CA1 subfield (Kerchner et al, 2014) of the hippocampus (Donix et al, 2010a, Chiang et al, 2011, O'Dwyer et al, 2012, Taylor et al, 2014, although contrasting results were published as well (Jack et al, 1998, Du et al, 2006, Schuff et al, 2009, Taylor et al, 2014. Moreover, higher cortical betaamyloid deposition (Reiman et al, 2009, Morris et al, 2010, glucose hypometabolism in brain regions typically impaired in AD (Rimajova et al, 2008, Fouquet et al, 2014 and changes in brain function during an encoding memory task (Filippini et al, 2011) were previously described in elderly cognitive intact individuals carrying the APOE ε4 allele.…”

Section: Introductionmentioning

confidence: 99%

Disrupted white matter structural networks in healthy older adult APOE ε4 carriers – An international multicenter DTI study

et al. 2017

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The ε4 allelic variant of the Apolipoprotein E gene (APOE ε4) is the best-established genetic risk factor for late-onset Alzheimer's disease (AD). White matter (WM) microstructural damages measured with Diffusion Tensor Imaging (DTI) represent an early sign of fiber tract disconnection in AD. We examined the impact of APOE ε4 on WM microstructure in elderly individuals from the multicenter European DTI Study on Dementia. Voxelwise statistical analysis of fractional anisotropy (FA), mean diffusivity, radial and axial diffusivity (MD, radD and axD respectively) was carried out using Tract-Based Spatial Statistics. Seventy-four healthy elderly individuals - 31 APOE ε4 carriers (APOE ε4+) and 43 APOE ε4 non-carriers (APOE ε4-) -were considered for data analysis. All the results were corrected for scanner acquisition protocols, age, gender and for multiple comparisons. APOE ε4+ and APOE ε4- subjects were comparable regarding sociodemographic features and global cognition. A significant reduction of FA and increased radD was found in the APOE ε4+ compared to the APOE ε4- in the cingulum, in the corpus callosum, in the inferior fronto-occipital and in the inferior longitudinal fasciculi, internal and external capsule. APOE ε4+, compared to APOE ε4- showed higher MD in the genu, right internal capsule, superior longitudinal fasciculus and corona radiate. Comparisons stratified by center supported the results obtained on the whole sample. These findings support previous evidence in monocentric studies indicating a modulatory role of APOE ɛ4 allele on WM microstructure in elderly individuals at risk for AD suggesting early vulnerability and/or reduced resilience of WM tracts involved in AD.

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“…This led to the concept of preclinical AD [ 5 ], which has now been validated in autopsy studies of non-demented elderly subjects with neuropathological evidence of AD [ 6 – 10 ], brain imaging studies [ 11 – 19 ], amyloid detection [ 20 ], and neuropsychological studies [ 21 , 22 ]. Surface-based subregional structure analysis may offer additional benefits [ 17 , 23 – 26 ], such as better visualization and increased statistical power, especially when detecting subtle genetic effects. As the paradigm in experimental therapeutics shifts toward earlier intervention and prevention, enrichment of treatment cohorts with APOE e4 carriers may improve diagnostic accuracy and may make it faster to evaluate treatments for preclinical AD [ 27 , 28 ].…”

Section: Introductionmentioning

confidence: 99%

Influence of APOE Genotype on Hippocampal Atrophy over Time - An N=1925 Surface-Based ADNI Study

Shi

Gutman

et al. 2016

PLoS ONE

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The apolipoprotein E (APOE) e4 genotype is a powerful risk factor for late-onset Alzheimer’s disease (AD). In the Alzheimer’s Disease Neuroimaging Initiative (ADNI) cohort, we previously reported significant baseline structural differences in APOE e4 carriers relative to non-carriers, involving the left hippocampus more than the right—a difference more pronounced in e4 homozygotes than heterozygotes. We now examine the longitudinal effects of APOE genotype on hippocampal morphometry at 6-, 12- and 24-months, in the ADNI cohort. We employed a new automated surface registration system based on conformal geometry and tensor-based morphometry. Among different hippocampal surfaces, we computed high-order correspondences, using a novel inverse-consistent surface-based fluid registration method and multivariate statistics consisting of multivariate tensor-based morphometry (mTBM) and radial distance. At each time point, using Hotelling’s T2 test, we found significant morphological deformation in APOE e4 carriers relative to non-carriers in the full cohort as well as in the non-demented (pooled MCI and control) subjects at each follow-up interval. In the complete ADNI cohort, we found greater atrophy of the left hippocampus than the right, and this asymmetry was more pronounced in e4 homozygotes than heterozygotes. These findings, combined with our earlier investigations, demonstrate an e4 dose effect on accelerated hippocampal atrophy, and support the enrichment of prevention trial cohorts with e4 carriers.

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The apolipoprotein E epsilon 4 allele is associated with ventricular expansion rate and surface morphology in dementia and normal aging

Cited by 28 publications

References 61 publications

Longitudinal brain imaging in preclinical Alzheimer disease: impact of APOE ε4 genotype

Longitudinal brain imaging in preclinical Alzheimer disease: impact of APOE ε4 genotype

Disrupted white matter structural networks in healthy older adult APOE ε4 carriers – An international multicenter DTI study

Influence of APOE Genotype on Hippocampal Atrophy over Time - An N=1925 Surface-Based ADNI Study

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