ArticleAlzheimer's research & therapy2021
The association of APOE ε4 with cognitive function over the adult life course and incidence of dementia: 20 years follow-up of the Whitehall II study.
Article in Alzheimer's research & therapy, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 126 papers, 2 of them syntheses that pooled it.
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Who cites it
126 citing papers in PubMed, 2 syntheses or guidelines pooled it, 158 citations in OpenAlex.
- Biomarkers associated with cognitive impairment in post-traumatic stress disorder: A systematic review of current evidence.Ageing research reviews · 2024Pooled it
- Meta-analysis of age-related cognitive decline reveals a novel locus for the attention domain and implicates a COVID-19-related gene for global cognitive function.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2023Pooled it
- Mixture of organic pollutants is associated with cognitive aging.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2026Trial
- Positive affect disrupts neurodegeneration effects on cognitive training plasticity in older adults.Social cognitive and affective neuroscience · 2024Trial
- Longitudinal effects of cerebrovascular reactivity and cerebral pulsatility in cognitively intact older adults with APOE4: links with cognition.GeroScience · 2026Article
- Sex-Specific Structural Vulnerability in Alzheimer's Disease: Insights from APOE ε 4-Negative Patients.Life (Basel, Switzerland) · 2026Article
- The Association BetweenNeurology. Genetics · 2026Article
- Higher baseline CSF cortisol is associated with adverse 24-month tau-related, neuroimaging, and cognitive outcomes across the Alzheimer's disease continuum.European geriatric medicine · 2026Article
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- Association between sleep inertia and cognitive performance among older adults in the Wisconsin Sleep Cohort study.Journal of clinical sleep medicine : JCSM : official publication of the American Academy of Sleep Medicine · 2026Article
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- Dementia risk factor assessment in a local Alzheimer's prevention population: a German cross-sectional, observational study.The journal of prevention of Alzheimer's disease · 2026Observational
- The physiological effects of APOE genotype in healthy young/middle-aged individuals.Biological reviews of the Cambridge Philosophical Society · 2026Article
- Genetic risk of Alzheimer's disease is associated with loss of brain network segregation in midlife.Communications biology · 2026Article
- Nonlinear kernel-based high-dimensional inference for set-based genetic association studies.Briefings in bioinformatics · 2026Article
- Lecanemab appropriate use recommendations for clinical practice in the UK.Journal of neurology, neurosurgery, and psychiatry · 2026Review
- TOMM40 suppression promotes neuronal cholesterol imbalance and molecular and behavioral phenotypes of Alzheimer's disease.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2026Article
- Genetic and epigenetic insights into perioperative neurocognitive disorders: a narrative review.British journal of anaesthesia · 2026Review
- Plasma amyloid-β predicts amyloid-β accumulation in PET A- non-demented participants.Journal of Alzheimer's disease : JAD · 2026Article
66 more citing papers are in PubMed but not listed here.
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Authors and funding
9 authors at 2 institutions in 2 countries.
Funding
Abstract
backgroundApproximately 25% of the general population carries at least one ε4 allele of the Apolipoprotein E (APOE ε4), the strongest genetic risk factor for late onset Alzheimer's disease. Beyond its association with late-onset dementia, the association between APOE ε4 and change in cognition over the adult life course remains uncertain. This study aims to examine whether the association between Apolipoprotein E (APOE) ε4 zygosity and cognition function is modified between midlife and old age.
methodsA cohort study of 5561 participants (mean age 55.5 (SD = 5.9) years, 27.1% women) with APOE genotyping and repeated cognitive tests for reasoning, memory, and semantic and phonemic fluency, during a mean (SD) follow-up of 20.2 (2.8) years (the Whitehall II study). We used joint models to examine the association of APOE genotype with cognitive function trajectories between 45 and 85 years taking drop-out, dementia, and death into account and Fine and Gray models to examine associations with dementia.
resultsCompared to non-carriers, heterozygote (prevalence 25%) and homozygote (prevalence 2%) APOE ε4 carriers had increased risk of dementia, sub-distribution hazard ratios 2.19 (95% CI 1.73, 2.77) and 5.97 (95% CI 3.85, 9.28) respectively. Using data spanning 45-85 years with non-ε4 carriers as the reference, ε4 homozygotes had poorer global cognitive score starting from 65 years; ε4 heterozygotes had better scores between 45 and 55 years, then no difference until poorer cognitive scores from 75 years onwards. In analysis of individual cognitive tests, better cognitive performance in the younger ε4 heterozygotes was primarily attributable to executive function.
conclusionsBoth heterozygous and homozygous ε4 carriers had poorer cognition and greater risk of dementia at older ages. Our findings show some support for a complex antagonist pleiotropic effect of APOE ε4 heterozygosity over the adult life course, characterized by cognitive advantage in midlife.
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