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Research Paper|Volume 13, Issue 7|pp 9277—9329

Multiomics integrative analysis identifies APOE allele-specific blood biomarkers associated to Alzheimer’s disease etiopathogenesis

Laura Madrid1, Sonia Moreno-Grau2,3, Shahzad Ahmad4, Antonio González-Pérez1, Itziar de Rojas2,3, Rui Xia5, Pamela V. Martino Adami6, Pablo García-González2, Luca Kleineidam6,7,8, Qiong Yang9, Vincent Damotte10, Joshua C. Bis11, Fuensanta Noguera-Perea12, Céline Bellenguez10, Xueqiu Jian5, Juan Marín-Muñoz12, Benjamin Grenier-Boley10, Adela Orellana2,3, M. Arfan Ikram4, Philippe Amouyel10, Claudia L. Satizabal13,14, Alzheimer’s Disease Neuroimaging Initiative (ADNI)*, EADI consortium, CHARGE consortium, GERAD consortium, GR@ACE/DEGESCO consortium, Luis Miguel Real15,16, Carmen Antúnez-Almagro12, Anita DeStefano7,14, Alfredo Cabrera-Socorro17, Rebecca Sims18, Cornelia M. Van Duijn4, Eric Boerwinkle19, Alfredo Ramírez6,7,8, Myriam Fornage5, Jean-Charles Lambert10, Julie Williams18,20, Sudha Seshadri13,14, ADAPTED consortium, Janina S. Ried21, Agustín Ruiz2,3, Maria Eugenia Saez1
  • 1Andalusion Bioiformatics Research Centre (CAEBi), Sevilla, Spain
  • 2Research Center and Memory Clinic Fundació ACE, Institut Català de Neurociències Aplicades, Universitat Internacional de Catalunya, Barcelona, Spain
  • 3CIBERNED, Network Center for Biomedical Research in Neurodegenerative Diseases, National Institute of Health Carlos III, Madrid, Spain
  • 4Department of Epidemiology, Erasmus Medical Centre, Rotterdam, The Netherlands
  • 5Institute of Molecular Medicine and Human Genetics Center, University of Texas Health Science Center at Houston, Houston, TX 77030, USA
  • 6Division of Neurogenetics and Molecular Psychiatry, Department of Psychiatry and Psychotherapy, Medical Faculty, University of Cologne, Cologne, Germany
  • 7Department of Neurodegenerative Diseases and Geriatric Psychiatry, University Hospital Bonn, Bonn, Germany
  • 8German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany
  • 9Department of Biostatistics, Boston University School of Public Health, Boston, MA 02118, USA
  • 10University Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1167-RID-AGE-Facteurs de Risque Et Déterminants Moléculaires des Maladies Liées au Vieillissement, Lille, France
  • 11Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA 98195, USA
  • 12Unidad de Demencias, Hospital Clínico Universitario Virgen de la Arrixaca, Carretera de Madrid-Cartagena s/n, 30120 El Palmar, Murcia, España
  • 13Glenn Biggs Institute for Alzheimer's and Neurodegenerative Diseases, UT Health San Antonio, San Antonio, TX 78229, USA
  • 14Department of Neurology, Boston University School of Medicine, Boston, MA 02118, USA
  • 15Unit of Infectious Diseases and Microbiology, Hospital Universitario de Valme, Sevilla, Spain
  • 16Department of Surgery, Biochemistry and Immunology, University of Malaga, Spain
  • 17Janssen Research and Development, a Division of Janssen Pharmaceutica N.V., Beerse, Belgium
  • 18Division of Psychological Medicine and Clinical Neuroscience, School of Medicine, Cardiff University, Cardiff, UK
  • 19Department of Epidemiology, Human Genetics, and Environmental Sciences, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA
  • 20UKDRI@Cardiff, School of Medicine, Cardiff University, Cardiff, UK
  • 21AbbVie Deutschland GmbH & Co. KG, Genomics Research Center, Knollstrasse, Ludwigshafen, Germany
* Data used in preparation of this article were obtained from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database (adni.loni.usc.edu). As such, the investigators within the ADNI contributed to the design and implementation of ADNI and/or provided data but did not participate in analysis or writing of this report. A complete listing of ADNI investigators can be found at: http://adni.loni.usc.edu/wp-content/uploads/how_to_apply/ADNI_Acknowledgement_List.pdf
Received: February 3, 2021Accepted: March 26, 2021Published: April 12, 2021
https://doi.org/10.18632/aging.202950

Copyright: © 2021 Madrid et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Abstract

Alzheimer’s disease (AD) is the most common form of dementia, currently affecting 35 million people worldwide. Apolipoprotein E (APOE) ε4 allele is the major risk factor for sporadic, late-onset AD (LOAD), which comprises over 95% of AD cases, increasing the risk of AD 4-12 fold. Despite this, the role of APOE in AD pathogenesis is still a mystery. Aiming for a better understanding of APOE-specific effects, the ADAPTED consortium analysed and integrated publicly available data of multiple OMICS technologies from both plasma and brain stratified by APOE haplotype (APOE2, APOE3 and APOE4). Combining genome-wide association studies (GWAS) with differential mRNA and protein expression analyses and single-nuclei transcriptomics, we identified genes and pathways contributing to AD in both APOE dependent and independent fashion. Interestingly, we characterised a set of biomarkers showing plasma and brain consistent protein profiles and opposite trends in APOE2 and APOE4 AD cases that could constitute screening tools for a disease that lacks specific blood biomarkers. Beside the identification of APOE-specific signatures, our findings advocate that this novel approach, based on the concordance across OMIC layers and tissues, is an effective strategy for overcoming the limitations of often underpowered single-OMICS studies.