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Scientific Summary

Alzheimer’s disease (AD) is a lethal neurodegenerative disease that affects brain integrity and functioning, resulting in progressive cognitive deterioration. Previous work indicates that epigenetic mechanisms including DNA (hydroxy)methylation represent critical factors in the pathogenesis of AD. Moreover, the early occurrence of various neuropsychological symptoms and novel neuropathological findings suggest a key role for the brainstem, particularly serotonin (5-HT)- and noradrenaline (NA)-specific neurons.

Therefore, we hypothesize that epigenetic dysregulation in the brainstem has a critical role in the early pathogenesis of AD and aim to elucidate the exact role of DNA (hydroxy)methylation within the brainstem in the development and progression of AD, by addressing these objectives:

  1. To identify AD-specific DNA (hydroxy)methylome profiles in the brainstem using post-mortem human brain tissue derived from well characterised AD patients, and age- and sex-matched controls
  2. To investigate the relationship between AD-specific DNA methylation signatures in the brainstem and in peripheral blood samples of the same individuals.
  3. To determine the predictive (biomarker) value of selected epigenetic signatures in well-characterised longitudinal aging cohorts, including individuals suffering from Mild Cognitive Impairment (MCI).
  4. To test for causal relations by modulating selected epigenetic marks in a novel model for AD using inducible pluripotent stem cells (iPSCs) derived from blood of AD patients and age-matched controls.

These objectives will be addressed within our cross-disciplinary network, through the use of established large human cohorts. The consortium will link the epigenetic profiles with cognitive dysfunction, AD-related neuropathology, gene variants regulating 5-HT and NA-function (Objectives I & II). For biomarker discovery, blood epigenetic signatures of aging individuals will be linked to subsequent cognitive decline, MCI-AD conversion and depression (Objective III). The putative signatures will also be compared to established (more invasive) biomarkers to determine their validity. By making use of iPSCs (Objective IV), the project will furthermore test whether i) neurons derived from iPSCs of AD patients develop an AD-characteristic molecular/epigenetic and cellular phenotype when exposed to AD brain extracts or glucocorticoids (GCs), and ii) epigenetic editing of candidate genes (from Objectives I and II) within 5-HT and NA neurons generated from iPSCs can reverse AD-specific phenotypes. 

 The comprehensive approach of this project integrates classical and new views on AD, and will fill the vital gap in our understanding of the links between epigenetic dysregulation and the 5-HT and NA neurotransmitter systems in the pathophysiology of AD. Thereby, the EPI-AD project will identify novel targets to better diagnose, prevent, attenuate or possibly reverse the pathophysiology of AD.