The association of APOE ε4 with cognitive function over the adult life course and incidence of dementia: 20years follow-up of the Whitehall II study

BackgroundApproximately 25% of the general population carries at least one epsilon 4 allele of the Apolipoprotein E (APOE epsilon 4), the strongest genetic risk factor for late onset Alzheimer's disease. Beyond its association with late-onset dementia, the association between APOE epsilon 4 and change in cognition over the adult life course remains uncertain. This study aims to examine whether the association between Apolipoprotein E (APOE) epsilon 4 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 85years 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 epsilon 4 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 45-85years with non-epsilon 4 carriers as the reference, epsilon 4 homozygotes had poorer global cognitive score starting from 65years; epsilon 4 heterozygotes had better scores between 45 and 55years, then no difference until poorer cognitive scores from 75years onwards. In analysis of individual cognitive tests, better cognitive performance in the younger epsilon 4 heterozygotes was primarily attributable to executive function.ConclusionsBoth heterozygous and homozygous epsilon 4 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 epsilon 4 heterozygosity over the adult life course, characterized by cognitive advantage in midlife.