Alzheimer´s disease (AD) is an incurable progressive neurodegenerative disorder in the elderly population worldwide. However, despite tremendous effort, the initial trigger of AD initiation that likely happens decades before the AD diagnosis is still unknown. And while the current body of research supports the concept that protein aggregation initiates the onset of AD, failure of over 413 clinical trials performed thus far that aimed to treat AD highlights the importance of introducing novel analytical strategies and methods to explore this disease from a new unbiased perspective. Therefore, the overall objective of this project is to determine which molecules, molecular pathways, and cell types are altered during the initial phase of AD development and use this knowledge to validate markers (and possibly “druggable targets”) of early disease onset. Specifically, we aim to 1) perform single-cell sequencing of our established functional AD-iPSCs-based model of brain organoids in the timeline experiments; 2) use unbiased data analysis to reveal molecules, molecular pathways, and cell types that are altered during the initiation of AD pathogenesis and pinpoint the relevant AD-driver change(s); and 3) evaluate if any of these novel findings could be used as early disease onset marker or possibly as AD drug-targets and perform functional studies of selected molecules. To this date, such single-cell seq analysis of AD-brain organoids has not been performed, nor has any of the available single-cell seq research from post-mortem AD-brains addressed the initial steps leading to the manifestation of AD pathology. Thus we believe that this project could significantly contribute to solving the initial trigger that stands behind the early steps of AD pathogenesis.

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