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.
Level 3 - non-randomized controlled study
Prospective longitudinal cohort study with repeated measures over 20 years
PubMed 33397450 · doi:10.1186/s13195-020-00740-0
What was done
A prospective cohort analysis of 5,561 participants (mean age 55.5 [SD = 5.9] years, 27.1% women) from the Whitehall II study with APOE genotyping and repeated cognitive tests (reasoning, memory, semantic and phonemic fluency) over a mean follow-up of 20.2 (SD = 2.8) years. Joint models evaluated cognitive trajectories from ages 45 to 85 taking into account drop-out, dementia, and death; Fine and Gray models assessed dementia risk.
What was found
Compared to non-carriers, APOE ε4 heterozygotes (25% prevalence) and homozygotes (2% prevalence) had higher dementia risk, with sub-distribution hazard ratios of 2.19 (95% CI 1.73, 2.77) and 5.97 (95% CI 3.85, 9.28), respectively. Homozygotes showed poorer global cognitive scores starting at age 65. Heterozygotes showed better global cognitive scores between ages 45 and 55 (primarily driven by executive function), no difference between 55 and 75, and poorer scores from age 75 onward.
Why it matters
These longitudinal findings provide support for antagonistic pleiotropy in APOE ε4 heterozygotes, characterized by a midlife cognitive advantage (executive function) followed by late-life cognitive decline and elevated dementia risk.
Limits
The study population was limited to British civil servants with low female representation (27.1%), limiting generalizability. The homozygote group was small (2% of participants, approximately 111 individuals).
Cited by
- supports In some populations, 15% to 25% of individuals carry one copy of the APOE4 allele, and 2% to 5% carry two copies.