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


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:
    Brain 07/2015; 138(Pt 9). DOI:10.1093/brain/awv191 · 9.20 Impact Factor
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    • "Genetic factors such as Apolipoprotein E (APOE) genotype might influence EOAD and LOAD forms. The presence of the APOE ε4 allele is a risk factor for LOAD (Blacker and Tanzi, 1998; Meyer et al., 1998) and has been suggested to modulate the disease onset and expression (van der Flier et al., 2011; Wolk et al., 2010). In EOAD, conversely, other genes such as APP, PSEN1, and PSEN2 (Raux et al., 2005; Rovelet-Lecrux et al., 2006) could be involved. "
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    ABSTRACT: Late-onset and early-onset Alzheimer's disease (LOAD, EOAD) affect different neural systems and may be separate nosographic entities. The most striking differences are in the medial temporal lobe, severely affected in LOAD and relatively spared in EOAD. We assessed amygdalar morphology and volume in 18 LOAD and 18 EOAD patients and 36 aged-matched controls and explored their relationship with the hippocampal volume. Three-dimensional amygdalar shape was reconstructed with the radial atrophy mapping technique, hippocampal volume was measured using a manual method. Atrophy was greater in LOAD than EOAD: 25% versus 17% in the amygdala and 20% versus 13% in the hippocampus. In the amygdala, LOAD showed significantly greater tissue loss than EOAD in the right dorsal central, lateral, and basolateral nuclei (20%-30% loss, p < 0.03), all known to be connected to limbic regions. In LOAD but not EOAD, greater hippocampal atrophy was associated with amygdalar atrophy in the left dorsal central and medial nuclei (r = 0.6, p < 0.05) also part of the limbic system. These findings support the notion that limbic involvement is a prominent feature of LOAD but not EOAD.
    Neurobiology of aging 03/2014; 35(9). DOI:10.1016/j.neurobiolaging.2014.03.009 · 5.01 Impact Factor
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    • "Fully pre-processed scans were downloaded for analysis. T1 image volumes were examined quantitatively by a cortical surface-based reconstruction and analysis of cortical thickness, using a hypothesis-driven approach as described in multiple previous publications (Bakkour et al., 2009; Dickerson et al., 2009, 2011; Wolk et al., 2010). Briefly, we utilized nine regions of interest (ROIs, see Figure 1) previously determined to be associated with AD, the " cortical signature " of AD (Bakkour et al., 2009; Dickerson et al., 2009). "
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    ABSTRACT: Objective: New diagnostic criteria for mild cognitive impairment (MCI) due to Alzheimer's disease (AD) have been developed using biomarkers aiming to establish whether the clinical syndrome is likely due to underlying AD. We investigated the utility of magnetic resonance imaging (MRI) and cerebrospinal fluid (CSF) biomarkers in predicting progression from amnesic MCI to dementia, testing the hypotheses that (1) markers of amyloid and neurodegeneration provide distinct and complementary prognostic information over different time intervals, and that (2) evidence of neurodegeneration in amyloid-negative MCI individuals would be useful prognostically. Methods: Data were obtained from the ADNI-1 (Alzheimer's Disease Neuroimaging Initiative Phase 1) database on all individuals with a baseline diagnosis of MCI, baseline MRI and CSF data, and at least one follow-up visit. MRI data were processed using a published set of a priori regions of interest to derive a measure known as the ``AD signature,'' as well as hippocampal volume. The CSF biomarkers amyloid-β, total tau, and phospho tau were also examined. We performed logistic regression analyses to identify the best baseline biomarker predictors of progression to dementia over 1 or 3 years, and Cox regression models to test the utility of these markers for predicting time-to-dementia. Results: For prediction of dementia in MCI, the AD signature cortical thickness biomarker performed better than hippocampal volume. Although CSF tau measures were better than CSF amyloid-β at predicting dementia within 1 year, the AD signature was better than all CSF measures at prediction over this relatively short-term interval. CSF amyloid-β was superior to tau and AD signature at predicting dementia over 3 years. When CSF amyloid-β was dichotomized using previously published cutoff values and treated as a categorical variable, a multivariate stepwise Cox regression model indicated that both the AD signature MRI marker and the categorical CSF amyloid-β marker were useful in predicting time-to-event diagnosis of AD dementia. Conclusion: In amnesic MCI, short-term (1 year) prognosis of progression to dementia relates strongly to baseline markers of neurodegeneration, with the AD signature MRI biomarker of cortical thickness performing the best among MRI and CSF markers studied here. Longer-term (3 year) prognosis in these individuals was better predicted by a marker indicative of brain amyloid. Prediction of time-to-event in a survival model was predicted by the combination of these biomarkers. These results provide further support for emerging models of the temporal relationship of pathophysiologic events in AD and demonstrate the utility of these biomarkers at the prodromal stage of the illness.
    Frontiers in Aging Neuroscience 10/2013; 5:55. DOI:10.3389/fnagi.2013.00055 · 4.00 Impact Factor
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