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      APOE-ε4 Shapes the Cerebral Organization in Cognitively Intact Individuals as Reflected by Structural Gray Matter Networks

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          Gray matter networks (GMn) provide essential information on the intrinsic organization of the brain and appear to be disrupted in Alzheimer’s disease (AD). Apolipoprotein E ( APOE)-ε4 represents the major genetic risk factor for AD, yet the association between APOE-ε4 and GMn has remained unexplored. Here, we determine the impact of APOE-ε4 on GMn in a large sample of cognitively unimpaired individuals, which was enriched for the genetic risk of AD. We used independent component analysis to retrieve sources of structural covariance and analyzed APOE group differences within and between networks. Analyses were repeated in a subsample of amyloid-negative subjects. Compared with noncarriers and heterozygotes, APOE-ε4 homozygotes showed increased covariance in one network including primarily right-lateralized, parietal, inferior frontal, as well as inferior and middle temporal regions, which mirrored the formerly described AD-signature. This result was confirmed in a subsample of amyloid-negative individuals. APOE-ε4 carriers showed reduced covariance between two networks encompassing frontal and temporal regions, which constitute preferential target of amyloid deposition. Our data indicate that, in asymptomatic individuals, APOE-ε4 shapes the cerebral organization in a way that recapitulates focal morphometric alterations observed in AD patients, even in absence of amyloid pathology. This suggests that structural vulnerability in neuronal networks associated with APOE-ε4 may be an early event in AD pathogenesis, possibly upstream of amyloid deposition.

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          Most cited references 78

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          A fast diffeomorphic image registration algorithm.

          This paper describes DARTEL, which is an algorithm for diffeomorphic image registration. It is implemented for both 2D and 3D image registration and has been formulated to include an option for estimating inverse consistent deformations. Nonlinear registration is considered as a local optimisation problem, which is solved using a Levenberg-Marquardt strategy. The necessary matrix solutions are obtained in reasonable time using a multigrid method. A constant Eulerian velocity framework is used, which allows a rapid scaling and squaring method to be used in the computations. DARTEL has been applied to intersubject registration of 471 whole brain images, and the resulting deformations were evaluated in terms of how well they encode the shape information necessary to separate male and female subjects and to predict the ages of the subjects.
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            Toward defining the preclinical stages of Alzheimer's disease: recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease.

            The pathophysiological process of Alzheimer's disease (AD) is thought to begin many years before the diagnosis of AD dementia. This long "preclinical" phase of AD would provide a critical opportunity for therapeutic intervention; however, we need to further elucidate the link between the pathological cascade of AD and the emergence of clinical symptoms. The National Institute on Aging and the Alzheimer's Association convened an international workgroup to review the biomarker, epidemiological, and neuropsychological evidence, and to develop recommendations to determine the factors which best predict the risk of progression from "normal" cognition to mild cognitive impairment and AD dementia. We propose a conceptual framework and operational research criteria, based on the prevailing scientific evidence to date, to test and refine these models with longitudinal clinical research studies. These recommendations are solely intended for research purposes and do not have any clinical implications at this time. It is hoped that these recommendations will provide a common rubric to advance the study of preclinical AD, and ultimately, aid the field in moving toward earlier intervention at a stage of AD when some disease-modifying therapies may be most efficacious. Copyright © 2011. Published by Elsevier Inc.
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              A voxel-based morphometric study of ageing in 465 normal adult human brains.

              Voxel-based-morphometry (VBM) is a whole-brain, unbiased technique for characterizing regional cerebral volume and tissue concentration differences in structural magnetic resonance images. We describe an optimized method of VBM to examine the effects of age on grey and white matter and CSF in 465 normal adults. Global grey matter volume decreased linearly with age, with a significantly steeper decline in males. Local areas of accelerated loss were observed bilaterally in the insula, superior parietal gyri, central sulci, and cingulate sulci. Areas exhibiting little or no age effect (relative preservation) were noted in the amygdala, hippocampi, and entorhinal cortex. Global white matter did not decline with age, but local areas of relative accelerated loss and preservation were seen. There was no interaction of age with sex for regionally specific effects. These results corroborate previous reports and indicate that VBM is a useful technique for studying structural brain correlates of ageing through life in humans.

                Author and article information

                Cereb Cortex
                Cereb. Cortex
                Cerebral Cortex (New York, NY)
                Oxford University Press
                June 2020
                12 March 2020
                12 March 2020
                : 30
                : 7
                : 4110-4120
                [1 ] Barcelonaβeta Brain Research Center (BBRC) , Pasqual Maragall Foundation, 08005 Barcelona, Spain
                [2 ] Hospital del Mar Medical Research Institute (IMIM) , 08005 Barcelona, Spain
                [3 ] Centro de Investigación Biomédica en Red de Fragilidad y Envejecimiento Saludable (CIBERFES) , 28089 Madrid, Spain
                [4 ] Universitat Pompeu Fabra , 08002 Barcelona, Spain
                [5 ] Centro de Investigación Biomédica en Red de Bioingeniería , Biomateriales y Nanomedicina (CIBERBBN), 28089 Madrid, Spain
                [6 ] Global Brain Health Institute , University of California San Francisco, San Francisco, CA 94115, USA
                [7 ] Department of Psychiatry and Neurochemistry , Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, 41390 Mölndal, Sweden
                [8 ] Clinical Neurochemistry Laboratory , Sahlgrenska University Hospital, 41390 Mölndal, Sweden
                [9 ] UK Dementia Research Institute at UCL , WC1E 6BT London, UK
                [10 ] Department of Neurodegenerative Disease , UCL Institute of Neurology, WC1N 3BG London, UK
                Author notes
                Address correspondence to Raffaele Cacciaglia and Juan Domingo Gispert López, Barcelonaβeta Brain Research Center, Pasqual Maragall Foundation, Wellington 30, 08005 Barcelona, Spain. Email: rcacciaglia@ ; jdgispert@ .
                © The Author(s) 2020. Published by Oxford University Press.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (, which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact

                Page count
                Pages: 11
                Funded by: la Caixa;
                Award ID: 100010434
                Funded by: Alzheimer's Association, DOI 10.13039/100000957;
                Award ID: LCF/PR/GN17/50300004
                Funded by: TriBEKa Imaging Platform;
                Award ID: TriBEKa-17-519007
                Funded by: Universities and Research Secretariat;
                Funded by: Ministry of Business and Knowledge of the Catalan Government;
                Award ID: 2017-SGR-892
                Funded by: Spanish Ministry of Economy, and Competitiveness;
                Award ID: RYC-2013-13054
                Original Article


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