Age stratification corrects bias in estimated hazard of APOE genotype for Alzheimer's disease

Li Liu, Richard J. Caselli

    Research output: Contribution to journalArticle

    Abstract

    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.

    Original languageEnglish (US)
    Pages (from-to)602-608
    Number of pages7
    JournalAlzheimer's and Dementia: Translational Research and Clinical Interventions
    Volume4
    DOIs
    StatePublished - Jan 1 2018

    Fingerprint

    Apolipoproteins E
    Alzheimer Disease
    Alleles
    Genotype
    Age of Onset
    Apolipoprotein E4
    Population Genetics
    Proportional Hazards Models
    Cohort Studies
    Research Design
    Regression Analysis

    Keywords

    • Age dependency
    • Alzheimer's disease
    • APOE genotype
    • Disease risk
    • Young onset dementia

    ASJC Scopus subject areas

    • Clinical Neurology
    • Psychiatry and Mental health

    Cite this

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    title = "Age stratification corrects bias in estimated hazard of APOE genotype for Alzheimer's disease",
    abstract = "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.",
    keywords = "Age dependency, Alzheimer's disease, APOE genotype, Disease risk, Young onset dementia",
    author = "Li Liu and Caselli, {Richard J.}",
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    TY - JOUR

    T1 - Age stratification corrects bias in estimated hazard of APOE genotype for Alzheimer's disease

    AU - Liu, Li

    AU - Caselli, Richard J.

    PY - 2018/1/1

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    N2 - 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.

    AB - 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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    KW - Alzheimer's disease

    KW - APOE genotype

    KW - Disease risk

    KW - Young onset dementia

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    EP - 608

    JO - Alzheimer's and Dementia: Translational Research and Clinical Interventions

    JF - Alzheimer's and Dementia: Translational Research and Clinical Interventions

    SN - 2352-8737

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