Abstract
The identification of genetic risk variants in the GWAS-identified Alzheimer risk gene ABCA7 has been remarkably fruitful, with identification of >50 premature termination codon (PTC) variants, as well as a pathogenic variable number of tandem repeats (VNTR) expansion. While both types of risk variants are predicted to lead to a loss of function, interpretation of the effect of these alleles is challenging, due to a complex splicing pattern and poor correlation between transcript and protein levels, and lack of knowledge of the cell types and tissues in which ABCA7 variants exert their effect. We will combine long-read sequencing and spatial RNA and protein profiling on brain regions and patient-derived cell types to enhance insights of the cellular patterns of ABCA7 expression and splicing in relation to AD. A better understanding of the mode of action of ABCA7 risk alleles will in the long run benefit a significant portion of
those at risk of AD, whether through improved risk prediction or targeted intervention. At the shorter term, identification of the cell type(s) in which ABCA7 exerts its risk increasing effects and better insight in the link between transcript and protein expression will inform downstream in vitro modeling and deliver targets for therapy development. Identification of a biomarker for penetrance of ABCA7 risk alleles will benefit risk prediction in research as well as in a clinical setting.
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