From protection to risk: Differential effects of the APOE e4 allele across the lifespan in Down syndrome

• In Event: 3-098 - Variability within neurodevelopmental disorders: Insights from developmental studies

Integrative Statement

Introduction
Down syndrome (DS) is the most common known genetic cause of intellectual disability and is caused by the presence of an additional chromosome 21. Individuals with DS show a much higher prevalence of Alzheimer’s disease (AD) than typically developing individuals. This is likely due to the overexpression of genes on chromosome 21, particularly the amyloid precursor protein (APP) gene which has been associated with early onset AD in the general population. However, there is still a large amount of variability in the clinical presentation and age of onset of dementia in those with DS. Some of this variability has been explained by variation in the apolipoprotein (APOE) gene on chromosome 19. The e4 allele of APOE is associated with an increased risk for AD in both the typical population and individuals with DS. Even though AD emerges over the last few decades of life, the effect of APOE on development may already be detected in infancy. In fact, studies in typically developing individuals suggest that the same e4 allele which is later in life linked to AD risk may initially provide advantages over other variants of the gene. In typical development, e4-carriers were shown to have increased myelination compared to e4-non-carriers over the first two years of life. Myelination has been linked to faster reaction times. However, it is unclear whether e4 allele plays a protective role early in development in DS, where dementia risk is exaggerated.

Hypothesis
We hypothesized that e4 plays a protective role in young children with DS. The e4-carriers will show faster reaction times than e4-non-carriers.

Study population
Eighty children with genetically confirmed DS between 8 and 62 months of age participated in this study.

Methods
APOE genotype was determined using a Thermo Fisher Scientific Taqman assay for SNPs rs7412 and rs429358 (Waltham, MA, USA). The gap-overlap task was administered using an eye-tracker to measure speed of attentional disengagement.

Results
Twenty-three (29%) children were e4-carriers, 57 (71%) were e4-non-carriers, which reflects the distribution in the typical population. To understand the role of e4 in early development in DS, we constructed cross-sectional developmental trajectories (Thomas et al., 2009; see Figure 1). Both e4-carriers and e4-non-carriers showed faster reaction times as they got older. We compared the trajectories of the two groups using ANCOVA. There was a significant difference between the intercepts (partial eta-squared=.07), indicating that the reaction times of e4-carriers were faster. There was also a trend for interaction between group and age (partial eta-squared=.04), suggesting that even though e4-carriers show an overall reaction time advantage, improvement in reaction times over development may have a steeper slope for e4-non-carriers. This reflects reports on typically developing children suggesting shallower myelination trajectories in e4-carriers than e4-non-carriers.
To our knowledge, this is the first study showing that e4 can provide an advantage in early development in DS. Understanding the differential role of APOE over development is an important step towards future intervention and towards generating a more balanced view of risk and protective factors for lifespan development.

Authors

• Hana D'Souza, University of Cambridge & Birkbeck, University of London
  Presenting Author

• Luke Mason, Birkbeck, University of London
  Non-Presenting Author

• Emma Meaburn, Birkbeck, University of London
  Non-Presenting Author

• Kin Y Mok, UCL
  Non-Presenting Author

• John Hardy, UCL
  Non-Presenting Author

• Annette Karmiloff-Smith, Birkbeck, University of London
  Non-Presenting Author

• Denis Mareschal, Birkbeck, University of London
  Non-Presenting Author

• Michael S. C. Thomas, University of London
  Non-Presenting Author