Alzheimer’s disease (AD) is a devastating neurodegenerative disease that accounts for more than 70% of worldwide dementia cases. The rising AD prevalence in aging populations is posing a substantial economic and health challenge. Unfolding the events leading to the development of AD may guide drug and preventive treatment research. Recent advances in multi-omics technology enable us to disentangle the molecular mechanism underlying AD pathophysiology. I have used multi-omics layers to enhance further our understanding of the molecular pathways underlying AD risk and pathophysiology. In this thesis, I identified biological pathways that may contribute to early AD pathology. I also evaluated the role of proteins and metabolites in the circulation and their interaction with AD risk genes. I found elevated levels of the HAGH and CDH6 proteins in blood in pre-dementia cases in the Rotterdam Study, and findings were replicated in an independent cohort. Findings from this thesis also underscore the role of signaling lipids in the pathophysiology of AD. Finally, this thesis provides new insight into the determinants of the gut-liver-brain axis in AD.

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C.M. van Duijn (Cornelia) , N. Amin (Najaf)
Erasmus University Rotterdam
Genetic Epidemiology Unit