ArticleAlzheimer's & dementia (New York, N. Y.)2018
Age stratification corrects bias in estimated hazard of
Article in Alzheimer's & dementia (New York, N. Y.), 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers, 1 of them a synthesis that pooled it.
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Who cites it
20 citing papers in PubMed, 1 synthesis or guideline pooled it.
- Evaluation of the Genetic Variance of Alzheimer's Disease Explained by the Disease-Associated Chromosomal Regions.Journal of Alzheimer's disease : JAD · 2019Pooled it
- Neuronal APOE4-induced early hippocampal network hyperexcitability in Alzheimer's disease pathogenesis.Nature aging · 2026Article
- Comorbidity sequence, sex, and APOE-genotype forecast Alzheimer's disease diagnosis.Frontiers in medicine · 2026Article
- Neutrophil-to-lymphocyte ratio predicts early cognitive decline associated with tau pathology in Alzheimer's disease: a longitudinal study of the ADNI cohort.Frontiers in aging neuroscience · 2026Article
- Multisystem failure, tipping points, and risk of Alzheimer's disease.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2025Article
- Reviewing and Advocating for Data Disaggregation in Aging-Related Health Research: NIA Grants and Recommendations for Equity.The Gerontologist · 2025Article
- Potential Modifying Effect of theInternational journal of molecular sciences · 2023Article
- GBA and APOE Impact Cognitive Decline in Parkinson's Disease: A 10-Year Population-Based Study.Movement disorders : official journal of the Movement Disorder Society · 2022Article
- Article
- Relationship of APOE, age at onset, amyloid and clinical phenotype in Alzheimer disease.Neurobiology of aging · 2021Article
- Brain Renin-Angiotensin System as Novel and Potential Therapeutic Target for Alzheimer's Disease.International journal of molecular sciences · 2021Review
- Omics Data and Their Integrative Analysis to Support Stratified Medicine in Neurodegenerative Diseases.International journal of molecular sciences · 2021Review
- A novel age-informed approach for genetic association analysis in Alzheimer's disease.Alzheimer's research & therapy · 2021Article
- Molecular subtyping of Alzheimer's disease using RNA sequencing data reveals novel mechanisms and targets.Science advances · 2021Article
- Age-dependent effect of APOE and polygenic component on Alzheimer's disease.Neurobiology of aging · 2020Article
- The dynamics of biomarkers across the clinical spectrum of Alzheimer's disease.Alzheimer's research & therapy · 2020Article
- The Alzheimer's Disease Exposome.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2019Article
- α-synuclein in the pathophysiology of Alzheimer's disease.Molecular neurodegeneration · 2019Review
- Detecting time-varying genetic effects in Alzheimer's disease using a longitudinal genome-wide association studies model.Alzheimer's & dementia (Amsterdam, Netherlands)Article
- Article
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Abstract
introductionThe 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.
methodsIn 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.
resultsHazard 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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