Age stratification corrects bias in estimated hazard of APOE genotype for Alzheimer's disease
Open accessAbstract
Introduction: The apolipoprotein E (APOE) e4 allele is a major genetic risk factor of late‐onset Alzheimer's disease. However, its interaction with two other canonical risk factors, age and sex, is not clear. Previous studies have reported conflicting results on its differential effects in men and women, its association with young‐onset AD before the age of 65 years, and its significance in genetic admixture populations. In these studies, the hazard of the e4 allele was assumed to be constant during aging. However, this hypothesis has not been tested and its violation may lead to significant biases and contribute to such discrepant findings. Methods: In a prospective cohort of 4727 subjects, we performed Cox regression analysis of the association of the e4 allele with AD age of onset. We then performed diagnostics on the resulting model and tested if the hazard of the e4 allele violated the assumption of proportionality during aging. We examined whether incorporating age stratifications and time‐dependent coefficients could restore the proportionality. We then validated our findings in four independent cohorts. Results: Hazard of the e4 allele for AD was nonproportional. It took a stepwise decline around the age of 80 years for men and around the age of 75 years for women. By stratifying subjects into a younger group and an older group, we detected more consistent effects of the e4 allele across multiple independent cohorts. We also found that the e4 allele was a significant risk factor for young‐onset AD with age of onset before 65 years. Discussion: Age compositions of study cohorts can significantly bias the estimated effect of the APOE genotype. Studies of AD should consider hidden age structures among subjects and routinely employ appropriate age and sex stratification strategies or nonparametric modeling in experimental designs and data analysis. Finally, we argue that the e4 allele is a risk factor not only for late‐onset AD but also for young‐onset AD.
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The effects of APOE genotype on AD risk are significantly diminished in older individuals (>75 years, LOAD).
“This is also consistent with recent meta-analyses of AD that have shown that the effects of APOE genotype on AD risk are significantly diminished in older individuals (>75 years, LOAD) (41).”
From Molecular subtyping of Alzheimer’s disease using RNA sequencing data reveals novel mechanisms and targets (2021) · cites this paper as [41]
The Results report a statistically significant decline in the APOE ε4 hazard with age, supporting the central claim. But the transition was approximately 75 years for women and 80 years for men, not uniformly >75 years; the paper also presents analyses of multiple cohorts rather than a meta-analysis. The cited passages have no page numbers in our copy. (LLM, conf=0.87)
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- Authors
- Liu, L., & Caselli, R. J.
- Affiliations
- Mayo Clinic in Arizona (US)
- Corresponding author
- Liu, Li
- Caselli, Richard J.
- Venue
- Alzheimer's & Dementia: Translational Research & Clinical Interventions
- Publisher
- Wiley
- Published
- 2018-01
- Volume
- 4
- Issue
- 1
- Pages
- 602-608
- ISSN
- 2352-8737 (ISSN-L)
- PMC
- PMC6226550
- OpenAlex
- W2898796531
- Cited by
- 29
- References
- 34
- Citations by year
- 2026: 3 · 2025: 2 · 2024: 2 · 2023: 2 · 2022: 3 · 2021: 7 · 2020: 3 · 2019: 7
- FWCI
- 2.92
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Alzheimer s & Dementia Translational Research & Clinical Interventions (publishedVersion, cc-by-nc-nd)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Funders
- National Institute on Aging
- 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
- APOE ε4, Alzheimer's disease, age stratification, proportional hazards assumption, age of onset, early-onset Alzheimer's disease, sex differences, genetic risk factors, time-dependent coefficients
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