The association of APOE [epsilon]4 with cognitive function over the adult life course and incidence of dementia: 20 years follow-up of the Whitehall II study

• Published in: Alzheimer's research & therapy Vol. 13; no. 1
• Main Authors: Gharbi-Meliani, Amin, Dugravot, Aline, Sabia, Séverine, Regy, Melina, Fayosse, Aurore, Schnitzler, Alexis, Kivimäki, Mika, Singh-Manoux, Archana, Dumurgier, Julien
• Format: Journal Article
• Language: English
• Published: BioMed Central Ltd 04.01.2021
• Subjects: Aging; Apolipoproteins; Cognition; Dementia; Development and progression; Genetic aspects; Health aspects; Physiological aspects; Risk factors; France
• ISSN: 1758-9193; 1758-9193
• DOI: 10.1186/s13195-020-00740-0

Background Approximately 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. 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 [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 45-85 years with non-[epsilon]4 carriers as the reference, [epsilon]4 homozygotes had poorer global cognitive score starting from 65 years; [epsilon]4 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 [epsilon]4 heterozygotes was primarily attributable to executive function. Conclusions Both 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. Keywords: Apolipoprotein E, Cognitive aging, Cohort study, Dementia, Alzheimer's disease