Aims, Research Question and Hypothesis

We hypothesize that epigenetic dysregulation in the brainstem has a critical role in the pathogenesis of AD. The main aim of the project is therefore to establish the exact role of DNA (hydroxyl)methylation  within the brainstem 5-HT and NA neurotransmitter systems in the development and course of AD, which will be addressed by the following specific objectives (see also Figure 1):

1. To examine the AD-specific DNA (hydroxy)methylome in the brainstem using post-mortem brain tissue derived from AD patients and age-matched controls
2. To investigate the relationship between AD- specific DNA methylation signatures in the brain and peripheral blood.
3. To determine the predictive (biomarker) value of selected epigenetic signatures in two longitudinal aging cohorts, including individuals with MCI and subjects with subjective memory complaints.
4. To target selected epigenetic marks by means of an advanced experimental model system for AD using iPSCs derived from blood of AD patients and age-matched controls.

By integrating classical and pioneering hypotheses on the aetiology of AD, this translational, multi-level approach will identify novel (epigenetic-based) loci and pathways to be used in order to better diagnose, prevent, attenuate or possibly reverse AD’s pathophysiology.

Figure 1: Schematic overview of translational study design.