Unraveling Molecular Mechanisms Underlying Alzheimer’s disease and its Related Endophenotypes

Dementia and its most common type, Alzheimer’s disease (AD) is a devastating disease that afflicts millions worldwide. Still, there are no targeted preventive interventions or pharmacological treatments for AD available. This makes further unraveling the pathophysiology of AD to find new targets for treatment a global research priority. Genetic research has played a pivotal role to identify novel insights in the pathophysiology of AD and has influenced clinical diagnostics and treatment developments. Therefore, the overarching aim of the studies included in this thesis is to gain novel insights in the molecular and biological mechanisms underlying AD and its related endophenotypes using genetic research. The studies that make up this thesis are organized in chapters that all approach this goal from a different angle.

In chapter 2 I studied the mechanisms of known genetic risk factors of AD, translating their effects to clinically useable outcomes. In chapter 3 I studied genetic variants that are rare in the general population aiming to identify novel molecular targets that are involved in the pathophysiology of AD. AD is known to have a long pre-clinical phase in which there are no apparent clinical signs. Sub-clinical signs start to appear up to twenty years before the onset of clinical symptoms. These subclinical signs include amyloid-β depositions, brain changes and changes in circulating blood measures. In chapter 4 and 5 I aimed to identify and understand these so called AD-related (endo) phenotypes. I focused in chapter 4 on the genetic background of endophenotypes in brain measured with Magnetic Resonance Imaging (MRI) and studied circulating endophenotypes, namely Amyloid-β and metabolites, in chapter 5.

In conclusion the discoveries described in this thesis improve our understanding of AD and its endophenotypes, and I hope they will enable or facilitate the so necessary development of treatments, or interventions for this devastating disease.