Article

Alzheimer's Disease Neuroimaging Initiative. Apolipoprotein E (APOE) genotype has dissociable effects on memory and attentional-executive network function in Alzheimer's disease

Department of Neurology, University of Pennsylvania, Philadelphia, PA 19104, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 06/2010; 107(22):10256-61.
Source: PubMed

ABSTRACT

The epsilon4 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 epsilon4 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 epsilon4 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.

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Available from: Bradford Dickerson, Dec 13, 2013
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    • "The first description of a frontal variant of Alzheimer's disease was provided by Johnson et al. (1999) in three patients with early and predominant executive dysfunction in the face of amyloid plaque and neurofibrillary tangle pathology . Several subsequent studies have reported on a dysexecutive phenotype of Alzheimer's disease (Binetti et al., 1996; Back-Madruga et al., 2002; Snowden et al., 2007; Wolk et al., 2010; Dickerson et al., 2011; Mez et al., 2013), but only few included autopsy/biomarker-confirmed Alzheimer's disease patients. Other autopsy (Forman et al., 2006; Balasa et al., 2011; Mendez et al., 2013, Blennerhassett et al., 2014), clinical (Larner, 2006; Woodward et al., 2010), and case (Taylor et al., 2008; Habek et al., 2010; Herrero-San Martin et al., 2013) studies have shown that the spectrum of frontal variant Alzheimer's disease also comprises patients with early personality and behavioural changes such as disinhibition, apathy or compulsiveness. "
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    ABSTRACT: A 'frontal variant of Alzheimer's disease' has been described in patients with predominant behavioural or dysexecutive deficits caused by Alzheimer's disease pathology. The description of this rare Alzheimer's disease phenotype has been limited to case reports and small series, and many clinical, neuroimaging and neuropathological characteristics are not well understood. In this retrospective study, we included 55 patients with Alzheimer's disease with a behavioural-predominant presentation (behavioural Alzheimer's disease) and a neuropathological diagnosis of high-likelihood Alzheimer's disease (n = 17) and/or biomarker evidence of Alzheimer's disease pathology (n = 44). In addition, we included 29 patients with autopsy/biomarker-defined Alzheimer's disease with a dysexecutive-predominant syndrome (dysexecutive Alzheimer's disease). We performed structured chart reviews to ascertain clinical features. First symptoms were more often cognitive (behavioural Alzheimer's disease: 53%; dysexecutive Alzheimer's disease: 83%) than behavioural (behavioural Alzheimer's disease: 25%; dysexecutive Alzheimer's disease: 3%). Apathy was the most common behavioural feature, while hyperorality and perseverative/compulsive behaviours were less prevalent. Fifty-two per cent of patients with behavioural Alzheimer's disease met diagnostic criteria for possible behavioural-variant frontotemporal dementia. Overlap between behavioural and dysexecutive Alzheimer's disease was modest (9/75 patients). Sixty per cent of patients with behavioural Alzheimer's disease and 40% of those with the dysexecutive syndrome carried at least one APOE ε4 allele. We also compared neuropsychological test performance and brain atrophy (applying voxel-based morphometry) with matched autopsy/biomarker-defined typical (amnestic-predominant) Alzheimer's disease (typical Alzheimer's disease, n = 58), autopsy-confirmed/Alzheimer's disease biomarker-negative behavioural variant frontotemporal dementia (n = 59), and controls (n = 61). Patients with behavioural Alzheimer's disease showed worse memory scores than behavioural variant frontotemporal dementia and did not differ from typical Alzheimer's disease, while executive function composite scores were lower compared to behavioural variant frontotemporal dementia and typical Alzheimer's disease. Voxel-wise contrasts between behavioural and dysexecutive Alzheimer's disease patients and controls revealed marked atrophy in bilateral temporoparietal regions and only limited atrophy in the frontal cortex. In direct comparison with behavioural and those with dysexecutive Alzheimer's disease, patients with behavioural variant frontotemporal dementia showed more frontal atrophy and less posterior involvement, whereas patients with typical Alzheimer's disease were slightly more affected posteriorly and showed less frontal atrophy (P < 0.001 uncorrected). Among 24 autopsied behavioural Alzheimer's disease/dysexecutive Alzheimer's disease patients, only two had primary co-morbid FTD-spectrum pathology (progressive supranuclear palsy). In conclusion, behavioural Alzheimer's disease presentations are characterized by a milder and more restricted behavioural profile than in behavioural variant frontotemporal dementia, co-occurrence of memory dysfunction and high APOE ε4 prevalence. Dysexecutive Alzheimer's disease presented as a primarily cognitive phenotype with minimal behavioural abnormalities and intermediate APOE ε4 prevalence. Both behavioural Alzheimer's disease and dysexecutive Alzheimer's disease presentations are distinguished by temporoparietal-predominant atrophy. Based on the relative sparing of frontal grey matter, we propose to redefine these clinical syndromes as 'the behavioural/dysexecutive variant of Alzheimer's disease' rather than frontal variant Alzheimer's disease. Further work is needed to determine whether behavioural and dysexecutive-predominant presentations of Alzheimer's disease represent distinct phenotypes or a single continuum. © The Author (2015). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.
    Full-text · Article · Jul 2015 · Brain
    • "The first description of a frontal variant of Alzheimer's disease was provided by Johnson et al. (1999) in three patients with early and predominant executive dysfunction in the face of amyloid plaque and neurofibrillary tangle pathology . Several subsequent studies have reported on a dysexecutive phenotype of Alzheimer's disease (Binetti et al., 1996; Back-Madruga et al., 2002; Snowden et al., 2007; Wolk et al., 2010; Dickerson et al., 2011; Mez et al., 2013), but only few included autopsy/biomarker-confirmed Alzheimer's disease patients. Other autopsy (Forman et al., 2006; Balasa et al., 2011; Mendez et al., 2013, Blennerhassett et al., 2014), clinical (Larner, 2006; Woodward et al., 2010), and case (Taylor et al., 2008; Habek et al., 2010; Herrero-San Martin et al., 2013) studies have shown that the spectrum of frontal variant Alzheimer's disease also comprises patients with early personality and behavioural changes such as disinhibition, apathy or compulsiveness. "

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    • "In accordance with the increased risk for developing AD, healthy elderly individuals that posses the ε4 allele have higher rates of cognitive decline than noncarriers (Caselli et al. 2007) which is accompanied by increased rates of temporal lobe atrophy, mapping mainly to the MTL and to the entorhinal cortex and subiculum in particular (Honea et al. 2009; Donix et al. 2010) (Fig. 20.4). Structural MRI studies further showed that the dose-dependent and regionally specific effect of the ε4 allele on brain structure leads to distinguishable AD phenotypes (Wolk and Dickerson 2010; Morgen et al. 2013). Thus, among AD patients, ε4 carriers exhibit greater atrophy of the temporal lobes, whereas noncarriers have greater frontoparietal atrophy. "
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    ABSTRACT: Alzheimer’s disease (AD) is a progressive neurodegenerative brain disorder and the most common cause of dementia in the elderly. Neuroimaging techniques have revolutionized research on the pathogenetic processes in AD, as they allow tracking AD-related pathological changes in the living brain with ever-increasing detail. The most widely used MRI-based imaging techniques for the study of AD-related brain changes include structural MRI for assessment of gray matter atrophy, diffusion-weighted MRI for assessment of reduced white matter fiber integrity, and functional MRI for assessment of alterations in brain activation and functional network organization. In this chapter, we will describe how these imaging techniques have furthered our understanding of the specific pattern of structural and functional brain changes as they spread through the brain during AD pathogenesis and how these changes are associated with the expression of clinical symptoms. We will further describe how MRI-based technology is being used to study the neural mechanisms by which specific molecular, genetic, and lifestyle factors modify the risk for, and the clinical course of, AD. As a direct clinical application, increased knowledge about the characteristic brain changes in the course of AD pathogenesis can be used for the development of stage-specific disease biomarkers that increase the certainty of clinical diagnoses and may even allow predicting an individual’s risk for future cognitive decline and development of dementia. Finally, multimodal imaging approaches help to advance the study of disease mechanisms in AD through the assessment of interrelations among the diverse structural and functional brain changes and may further increase the accuracy of imaging-based diagnostic models by providing a more comprehensive picture of an individual’s pathologic state.
    Full-text · Chapter · Apr 2014
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