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.
Highlights
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
To address some of these limitations, we examined the relationship of homozygotes and heterozygotes APOE ε4 with cognitive decline from midlife to old age and incident dementia
There was no difference in cognitive scores at baseline between the APOE ε4/ε4 and ε3/ε3 homozygotes
Summary
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. The ε4 allele of the Apolipoprotein E (APOE) gene is the strongest genetic risk factor for late onset Alzheimer’s disease (AD) [1]. Case-control and longitudinal studies have examined the association of APOE with dementia, its association with cognitive decline over the adult life course remains debated [11, 12]. Much of the research on APOE is based on adults older than 65 years, followed for less than 10 years, making it difficult to ascertain how APOE shapes cognitive performance over the life course
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