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Genetic resilience to Alzheimer's disease in APOE ε4 homozygotes: A systematic review

  • Aamira J. Huq
    Correspondence
    Corresponding author. Tel.: +61 3 9342 7151; Fax: +61 3 9342 4267.
    Affiliations
    Department of Epidemiology and Preventive Medicine, School of Public Health and Preventive Medicine, Monash University, Melbourne, VIC, Australia

    Department of Genomic Medicine, Royal Melbourne Hospital, Department of Medicine, Royal Melbourne Hospital, University of Melbourne, Melbourne, VIC, Australia
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  • Peter Fransquet
    Affiliations
    Department of Epidemiology and Preventive Medicine, School of Public Health and Preventive Medicine, Monash University, Melbourne, VIC, Australia
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  • Simon M. Laws
    Affiliations
    Collaborative Genomics Group, Centre of Excellence for Alzheimer's Disease Research and Care, School of Medical and Health Sciences, Edith Cowan University, Joondalup, Western Australia, Australia

    School of Pharmacy and Biomedical Sciences, Faculty of Health Sciences, Curtin Health Innovation Research Institute, Curtin University, Bentley, WA, Australia
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  • Joanne Ryan
    Affiliations
    Department of Epidemiology and Preventive Medicine, School of Public Health and Preventive Medicine, Monash University, Melbourne, VIC, Australia
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  • Robert Sebra
    Affiliations
    Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
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  • Colin L. Masters
    Affiliations
    The Florey Institute, University of Melbourne, Parkville, Victoria, Australia
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  • Ingrid M. Winship
    Affiliations
    Department of Genomic Medicine, Royal Melbourne Hospital, Department of Medicine, Royal Melbourne Hospital, University of Melbourne, Melbourne, VIC, Australia
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  • Author Footnotes
    ∗ Joint senior authors.
    Paul A. James
    Footnotes
    ∗ Joint senior authors.
    Affiliations
    Department of Genomic Medicine, Royal Melbourne Hospital, Department of Medicine, Royal Melbourne Hospital, University of Melbourne, Melbourne, VIC, Australia
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  • Author Footnotes
    ∗ Joint senior authors.
    Paul Lacaze
    Footnotes
    ∗ Joint senior authors.
    Affiliations
    Department of Epidemiology and Preventive Medicine, School of Public Health and Preventive Medicine, Monash University, Melbourne, VIC, Australia
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  • Author Footnotes
    ∗ Joint senior authors.
Published:September 07, 2019DOI:https://doi.org/10.1016/j.jalz.2019.05.011

      Abstract

      Introduction

      Individuals with homozygosity for the apolipoprotein E (APOE) ε4 allele are in the highest risk category for late-onset Alzheimer's disease (LOAD). However, some individuals in this category do not develop LOAD beyond the age of 75 years, despite being at elevated genetic risk. These “resilient” individuals may carry protective genetic factors.

      Methods

      This study aimed to systematically review any previous studies that involved resilient APOE ε4 homozygotes and to identify possible modifying or protective genetic factors.

      Results

      Fifteen studies met our inclusion criteria and reported genetic factors contributing to reduced risk. We found that only two single nucleotide polymorphisms, CASP7 rs10553596 and SERPINA3 rs4934-A/A, had strong evidence.

      Discussion

      We found a paucity of studies adequately designed to discover protective genetic factors against LOAD. Many studies combined APOE ε4 homozygotes and heterozygotes together because of small sample sizes and used control populations too young to be clearly defined as controls for LOAD.

      Keywords

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