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

Abstract

Background: Approximately 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.

Methods: A 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.

Results: Compared 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.

Conclusions: Both 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.

Keywords: Alzheimer’s disease; Apolipoprotein E; Cognitive aging; Cohort study; Dementia.

Fig. 1

Flow chart of the study

Fig. 2

Global cognitive score over the adult life course as a function of number of APOE ε4 alleles. Analysis are undertaken using joint models, using age as time scale (age, age², and age³), and adjusted for sex, marital status, education level, occupation, and their interactions with time. a Global cognitive score trajectories according to the number of APOE ε4 alleles. b Difference in global cognitive score in APOE ε4 homozygotes and heterozygotes compared to non-ε4 carriers. Gray shaded intervals represent 95% confidence intervals of the estimates

Fig. 3

Difference in standardized cognitive tests of memory (a), reasoning (b), semantic (c), and phonemic fluency (d) in APOE ε4 heterozygotes and homozygotes compared to non-ε4 carriers. Analysis are undertaken using joint models, using age as time scale (age, age², and age³), and adjusted for sex, marital status, education level, occupation, and their interactions with time. Gray-shaded intervals represent 95% confidence intervals of the estimates