Genetic resilience to Alzheimer's disease in APOE ε4 homozygotes: A systematic review
Open accessAbstract
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.
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CASP7 rs10553596 and SERPINA3 rs4934-A/A have been suggested to confer resilience against Alzheimer disease in people homozygous for APOEε4 aged >75 years.
“CASP7 rs10553596 and SERPINA3 rs4934-A/A have also been suggested to confer resilience against AD in people homozygous for APOEε4 aged >75 years27.”
From Multifaceted roles of APOE in Alzheimer disease (2024) · cites this paper as [27]
Cites
Desikan, R. S., Fan, C. C., Wang, Y., Schork, A. J., Cabral, H. J., Cupples, L. A., Thompson, W. K., Besser, L., Kukull, W. A., Holland, D., et al. (2017) · PLoS Medicine · doi:10.1371/journal.pmed.1002258 · Cited by 395 · cited 1× · see citing works
“Large longitudinal studies of polygenic risk scores in AD have shown promise in their ability to predict the age of onset and risk of developing dementia [21,22].”
BackgroundA4POE*4-associated Alzheimer's disease risk is modified by α1–antichymotrypsin polymorphism
Kamboh, M. I., Sanghera, D. K., Ferrell, R. E., & DeKosky, S. T. (1995) · Nature Genetics · doi:10.1038/ng0895-486 · Cited by 336 · see citing works
<i>APOE</i> ε4: The most prevalent yet understudied risk factor for Alzheimer's disease
Michaelson, D. M. (2014) · Alzheimer's & Dementia · doi:10.1016/j.jalz.2014.06.015 · Cited by 331 · see citing works
Tesi, N., van der Lee, S. J., Hulsman, M., Jansen, I. E., Stringa, N., van Schoor, N., Meijers-Heijboer, H., Huisman, M., Scheltens, P., Reinders, M. J. T., et al. (2019) · European Journal of Human Genetics · doi:10.1038/s41431-018-0273-5 · Cited by 65 · see citing works
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APOE and Alzheimer’s disease: Advances in genetics, pathophysiology, and therapeutic approaches
Serrano-Pozo, A., Das, S., & Hyman, B. T. (2021) · The Lancet Neurology · doi:10.1016/s1474-4422(20)30412-9 · Cited by 1,037 · see citing works
Multifaceted roles of APOE in Alzheimer disease
Jackson, R. J., Hyman, B. T., & Serrano-Pozo, A. (2024) · Nature Reviews Neurology · doi:10.1038/s41582-024-00988-2 · Cited by 193 · see citing works
- Authors
- Huq, A. J., Fransquet, P., Laws, S. M., Ryan, J., Sebra, R., Masters, C. L., Winship, I. M., James, P. A., & Lacaze, P.
- Affiliations
- The Royal Melbourne Hospital (AU)
- Monash University (AU)
- Edith Cowan University (AU)
- Icahn School of Medicine at Mount Sinai (US)
- The University of Melbourne (AU)
- Corresponding author
- Huq, Aamira J.
- ORCID
- Venue
- Alzheimer's & Dementia
- Publisher
- Wiley
- Published
- 2019-09-07
- Volume
- 15
- Issue
- 12
- Pages
- 1612-1623
- ISSN
- 1552-5260 (ISSN-L)
- 1552-5279
- OpenAlex
- W2972234535
- Cited by
- 35
- References
- 4
- Citations by year
- 2026: 4 · 2025: 6 · 2024: 5 · 2023: 5 · 2022: 3 · 2021: 5 · 2020: 7
- FWCI
- 0.44
- Type
- journal article
- Language
- en
- Open access
- green
- figshare.com
- Locations
- Alzheimer s & Dementia (publishedVersion)
- PubMed (publishedVersion)
- Research Online (Edith Cowan University) (submittedVersion)
- Deakin Research Online (Deakin University) (submittedVersion)
- Figshare (submittedVersion, cc-by)
- Funders
- University of Melbourne (96756)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Keywords
- Alzheimer's disease
- MeSH terms
- Alleles, Alzheimer Disease, Homozygote, Humans, Risk Factors, Polymorphism, Single Nucleotide, Apolipoprotein E4, Protective Factors
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