<i>APOE-ε4 is associated with less frontal and more medial temporal lobe atrophy in AD</i>

Geroldi, Cristina; Pihlajamäki, Maija; Laakso, Mikko P.; DeCarli, Charles; Beltramello, Alberto; Bianchetti, Angelo; Soininen, Hilkka; Trabucchi, Marco; Frisoni, Giovanni B.

doi:10.1212/wnl.53.8.1825

Cited by 145 publications

(109 citation statements)

References 44 publications

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“…In contrast, another recent study surveying the whole brain using voxel-based morphometry identified relatively more prominent MTL atrophy in carriers but did not find areas where gray matter volume was greater in ε4 carriers than noncarriers (35). Finally, two older studies of select regions reported evidence of smaller frontal lobe volumes in noncarriers relative to carriers (19,21), but again with no psychometric differences, likely owing to small sample size.…”

Section: Resultsmentioning

confidence: 73%

“…Conflicting results have also been reported from the limited investigations of cortical anatomy, with some studies reporting no difference and others reporting more robust regional atrophy in ε4 carriers (20,23). Finally, there are a few reports of greater atrophy in noncarriers either in select regions, such as the frontal lobe, or in global measures of brain volume (17,(19)(20)(21).…”

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confidence: 99%

“…Autopsy and amyloid imaging studies have reported greater Aβ plaque deposition in carriers of the ε4 allele, even after controlling for disease severity (16). Quantitative neuroimaging investigations have reported greater medial temporal lobe (MTL) atrophy, particularly involving the hippocampus, in AD patients who are ε4 carriers vs. noncarriers (17)(18)(19)(20)(21), although this has not been a universal finding (22,23). Conflicting results have also been reported from the limited investigations of cortical anatomy, with some studies reporting no difference and others reporting more robust regional atrophy in ε4 carriers (20,23).…”

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confidence: 99%

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Apolipoprotein E (APOE) genotype has dissociable effects on memory and attentional–executive network function in Alzheimer’s disease

Wolk

Dickerson²

2010

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

215

178

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The ε4 allele of the apolipoprotein E (APOE) gene is the major genetic risk factor for Alzheimer's disease (AD), but limited work has suggested that APOE genotype may modulate disease phenotype. Carriers of the ε4 allele have been reported to have greater medial temporal lobe (MTL) pathology and poorer memory than noncarriers. Less attention has focused on whether there are domains of cognition and neuroanatomical regions more affected in noncarriers. Further, a major potential confound of prior in vivo studies is the possibility of different rates of clinical misdiagnosis for carriers vs. noncarriers. We compared phenotypic differences in cognition and topography of regional cortical atrophy of ε4 carriers (n = 67) vs. noncarriers (n = 24) with mild AD from the Alzheimer's Disease Neuroimaging Initiative, restricted to those with a cerebrospinal fluid (CSF) molecular profile consistent with AD. Between-group comparisons were made for psychometric tests and morphometric measures of cortical thickness and hippocampal volume. Carriers displayed significantly greater impairment on measures of memory retention, whereas noncarriers were more impaired on tests of working memory, executive control, and lexical access. Consistent with this cognitive dissociation, carriers exhibited greater MTL atrophy, whereas noncarriers had greater frontoparietal atrophy. Performance deficits in particular cognitive domains were associated with disproportionate regional brain atrophy within nodes of cortical networks thought to subserve these cognitive processes. These convergent cognitive and neuroanatomic findings in individuals with a CSF molecular profile consistent with AD support the hypothesis that APOE genotype modulates the clinical phenotype of AD through influence on specific large-scale brain networks.cognition | neuroimaging | dementia | cortical thickness | medial temporal lobe

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Section: Resultsmentioning

confidence: 73%

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confidence: 99%

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confidence: 99%

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Apolipoprotein E (APOE) genotype has dissociable effects on memory and attentional–executive network function in Alzheimer’s disease

Wolk

Dickerson²

2010

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

215

178

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“…Step 2 Step 3 why effects on global hippocampal volume are subtler, observed in some studies [4][5][6][7][8][9] but not others. [10][11][12] A particular strength of our study is the finding of a possible symptomatic consequence of APOE e4-associated CA1-SRLM thinning, which appeared to mediate the relationship between carrier status and the integrity of episodic memory.…”

Section: Resultsmentioning

confidence: 99%

APOE ε4 worsens hippocampal CA1 apical neuropil atrophy and episodic memory

et al. 2014

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Objectives: Using high-resolution structural MRI, we endeavored to study the relationships among APOE e4, hippocampal subfield and stratal anatomy, and episodic memory.Methods: Using a cross-sectional design, we studied 11 patients with Alzheimer disease dementia, 14 patients with amnestic mild cognitive impairment, and 14 age-matched healthy controls with no group differences in APOE e4 carrier status. Each subject underwent ultra-high-field 7.0-tesla MRI targeted to the hippocampus and neuropsychological assessment.Results: We found a selective, dose-dependent association of APOE e4 with greater thinning of the CA1 apical neuropil, or stratum radiatum/stratum lacunosum-moleculare (CA1-SRLM), a hippocampal subregion known to exhibit early vulnerability to neurofibrillary pathology in Alzheimer disease. The relationship between the e4 allele and CA1-SRLM thinning persisted after controlling for dementia severity, and the size of other hippocampal subfields and the entorhinal cortex did not differ by APOE e4 carrier status. Carriers also exhibited worse episodic memory function but similar performance in other cognitive domains compared with noncarriers. In a statistical mediation analysis, we found support for the hypothesis that CA1-SRLM thinning may link the APOE e4 allele to its phenotypic effects on memory. Conclusions:The APOE e4 allele segregated dose-dependently and selectively with CA1-SRLM thinning and worse episodic memory performance in a pool of older subjects across a cognitive spectrum. These findings highlight a possible role for this gene in influencing a critical hippocampal subregion and an associated symptomatic manifestation. Neurology ® 2014;82:691-697 GLOSSARY AD 5 Alzheimer disease; aMCI 5 amnestic mild cognitive impairment; ANOVA 5 analysis of variance; CA1-SP 5 CA1 stratum pyramidale; CA1-SRLM 5 CA1 stratum radiatum/lacunosum-moleculare; CDR 5 Clinical Dementia Rating; DG/CA3 5 dentate gyrus and CA3; ERC 5 entorhinal cortex; MTL 5 medial temporal lobe; NIA-AA 5 National Institute on Aging-Alzheimer's Association; OC 5 older control.ApoE influences the metabolism of b-amyloid, the major peptide constituent of amyloid plaques in Alzheimer disease (AD).1 The ApoE4 isoform confers an increased risk of sporadic late-onset AD dementia. 2,3Carriers of the APOE e4 allele who have AD dementia or its clinical precursor, amnestic mild cognitive impairment (aMCI), exhibit greater hippocampal volume loss than noncarriers in some studies, 4-9 although this finding is controversial. [10][11][12] Perhaps these divergent findings arise from disproportionate effects of the e4 allele on individual hippocampal subfields that are not always evident in global volumetric analyses.Specific effects of the APOE e4 allele on hippocampal subfields are of interest. AD-related neuropathology itself is subfield-and even strata-selective, affecting the CA1 subfield, including specifically the stratum radiatum/stratum lacunosum-moleculare (CA1-SRLM), before affecting the remainder of the hippocampus. [13][14][15...

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“…Structural imaging studies of AD patients have revealed morphological deficits in carriers of the ApoE4 allele versus noncarriers (Lehtovirta et al, 1995;Juottonen et al, 1998;Geroldi et al, 1999;Mori et al, 2002). In healthy elderly subjects, the ApoE4 allele is associated with diminished CNS glucose utilization (Reiman et al, 2004) and some studies have reported impairment in cognitive function (Deary et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

Automated ventricular mapping with multi-atlas fluid image alignment reveals genetic effects in Alzheimer's disease

Chou¹,

Leporé²,

Zubicaray

et al. 2008

NeuroImage

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We developed and validated a new method to create automated 3D parametric surface models of the lateral ventricles in brain MRI scans, providing an efficient approach to monitor degenerative disease in clinical studies and drug trials. First, we used a set of parameterized surfaces to represent the ventricles in four subjects' manually labeled brain MRI scans (atlases). We fluidly registered each atlas and mesh model to MRIs from 17 Alzheimer's disease (AD) patients and 13 age-and gendermatched healthy elderly control subjects, and 18 asymptomatic ApoE4-carriers and 18 age-and gender-matched non-carriers. We examined genotyped healthy subjects with the goal of detecting subtle effects of a gene that confers heightened risk for Alzheimer's disease. We averaged the meshes extracted for each 3D MR data set, and combined the automated segmentations with a radial mapping approach to localize ventricular shape differences in patients. Validation experiments comparing automated and expert manual segmentations showed that (1) the Hausdorff labeling error rapidly decreased, and (2) the power to detect disease-and gene-related alterations improved, as the number of atlases, N, was increased from 1 to 9. In surface-based statistical maps, we detected more widespread and intense anatomical deficits as we increased the number of atlases. We formulated a statistical stopping criterion to determine the optimal number of atlases to use. Healthy ApoE4-carriers and those with AD showed local ventricular abnormalities. This high-throughput method for morphometric studies further motivates the combination of genetic and neuroimaging strategies in predicting AD progression and treatment response.

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APOE-ε4 is associated with less frontal and more medial temporal lobe atrophy in AD

Abstract: We found smaller volumes in the temporal lobe regions but larger volumes in the frontal lobes with increasing APOE-e4 gene dose in AD patients. These data suggest a region-specific biological effect of the e4 allele in the brains of AD patients.

Cited by 145 publications

References 44 publications

Apolipoprotein E (APOE) genotype has dissociable effects on memory and attentional–executive network function in Alzheimer’s disease

Apolipoprotein E (APOE) genotype has dissociable effects on memory and attentional–executive network function in Alzheimer’s disease

APOE ε4 worsens hippocampal CA1 apical neuropil atrophy and episodic memory

Automated ventricular mapping with multi-atlas fluid image alignment reveals genetic effects in Alzheimer's disease

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