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

Aamira J Huq; Peter Fransquet; Simon M Laws; Joanne Ryan; Robert Sebra; Colin L Masters; Ingrid M Winship; Paul A James; Paul Lacaze

doi:10.1016/j.jalz.2019.05.011

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

Alzheimers Dement. 2019 Dec;15(12):1612-1623. doi: 10.1016/j.jalz.2019.05.011. Epub 2019 Sep 7.

Authors

Aamira J Huq¹, Peter Fransquet², Simon M Laws³, Joanne Ryan², Robert Sebra⁴, Colin L Masters⁵, Ingrid M Winship⁶, Paul A James⁶, Paul Lacaze²

Affiliations

¹ 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. Electronic address: Aamira.Huq@mh.org.au.
² Department of Epidemiology and Preventive Medicine, School of Public Health and Preventive Medicine, Monash University, Melbourne, VIC, Australia.
³ 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.
⁴ Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
⁵ The Florey Institute, University of Melbourne, Parkville, Victoria, Australia.
⁶ Department of Genomic Medicine, Royal Melbourne Hospital, Department of Medicine, Royal Melbourne Hospital, University of Melbourne, Melbourne, VIC, Australia.

PMID: 31506248
DOI: 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: APOE e4 homozygotes; Alzheimer's disease; CASP7; Genetic resilience; Resilience; SERPINA3.

Publication types

Research Support, Non-U.S. Gov't
Systematic Review

MeSH terms

Alleles
Alzheimer Disease* / epidemiology
Alzheimer Disease* / genetics
Apolipoprotein E4 / genetics*
Homozygote*
Humans
Polymorphism, Single Nucleotide
Protective Factors*
Risk Factors

Substances

Apolipoprotein E4