Methylomic profiling in trisomy 21 identifies cognition- and Alzheimer's disease-related dysregulation

Larissa Haertle, Tobias Mueller, Roy Lardenoije, Anna Maierhofer, Marcus Dittrich, Renzo J. M. Riemens, Samantha Stora, Mathilde Roche, Markus Leber, Steffi Riedel-Heller, Michael Wagner, Martin Scherer, Aime Ravel, Clotilde Mircher, Cecile Cieuta-Walti, Sophie Durand, Daniel L. A. van de Hove, Per Hoffmann, Alfredo Ramirez, Thomas HaafNady El Hajj, Andre Megarbane*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review


Background: Trisomy 21 (T21) is associated with intellectual disability that ranges from mild to profound with an average intellectual quotient of around 50. Furthermore, T21 patients have a high risk of developing Alzheimer's disease (AD) early in life, characterized by the presence of senile plaques of amyloid protein and neurofibrillary tangles, leading to neuronal loss and cognitive decline. We postulate that epigenetic factors contribute to the observed variability in intellectual disability, as well as at the level of neurodegeneration seen in T21 individuals.

Materials and Methods: A genome-wide DNA methylation study was performed using Illumina Infinium (R) MethylationEPIC BeadChips on whole blood DNA of 3 male T21 patients with low IQ, 8 T21 patients with high IQ (4 males and 4 females), and 21 age- and sex-matched control samples (12 males and 9 females) in order to determine whether DNA methylation alterations could help explain variation in cognitive impairment between individuals with T21. In view of the increased risk of developing AD in T21 individuals, we additionally investigated the T21-associated sites in published blood DNA methylation data from the AgeCoDe cohort (German study on Ageing, Cognition, and Dementia). AgeCoDe represents a prospective longitudinal study including non-demented individuals at baseline of which a part develops AD dementia at follow-up.

Results: Two thousand seven hundred sixteen differentially methylated sites and regions discriminating T21 and healthy individuals were identified. In the T21 high and low IQ comparison, a single CpG located in the promoter of PELI1 was differentially methylated after multiple testing adjustment. For the same contrast, 69 differentially methylated regions were identified. Performing a targeted association analysis for the significant T21-associated CpG sites in the AgeCoDe cohort, we found that 9 showed significant methylation differences related to AD dementia, including one in the ADAM10 gene. This gene has previously been shown to play a role in the prevention of amyloid plaque formation in the brain.

Conclusion: The differentially methylated regions may help understand the interaction between methylation alterations and cognitive function. In addition, ADAM10 might be a valuable blood-based biomarker for at least the early detection of AD.

Original languageEnglish
Article number195
Number of pages11
JournalClinical epigenetics
Issue number1
Publication statusPublished - 16 Dec 2019


  • Trisomy 21
  • DNA methylation
  • Intellectual disability
  • Down syndrome
  • Cognitive function
  • Alzheimer's disease
  • Infinium Methylation EPIC arrays


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