Toward precision medicine: modulation of ABCA7 associated risk of Alzheimer's disease by ancestry

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Abstract Ethnic and cultural diversity offers economic and societal benefits. It also poses challenges in therapeutic development and health care provision. However, ancestry has not been taken consistently into consideration until recently, when the need for precision medicine became apparent. There is therefore lack of research into ancestral differences in disease pathology and even of well-established approaches on how to investigate such differences. Mouse models do not seem to be suitable for studies of pathophysiology by ancestry. The purpose of this study is to elucidate how much loss of adenosine triphosphate binding cassette transporter subfamily A member 7 (ABCA7) affects amyloid β (Aβ) metabolism in individuals of European, African and East Asian ancestry using human induced pluripotent stem (iPS) cell-derived neurons. ABCA7 has been implicated as a risk factor in Alzheimer's disease (AD) pathology in many genome-wide association and genome sequencing studies in European, African and, to a lesser extent, East Asian ancestry. In preliminary data, we confirm observations from genetics and show that in a cohort of approximately 145 AD and control subjects of mostly European ancestry, individuals with very low ABCA7 levels exhibited accelerated AD pathogenesis. We also show that deletion of ABCA7 using CRISPR/Cas9 in iPS cell-derived neurons from individuals of European ancestry leads to an increase in Aβ secretion. Finally, we confirm that ABCA7 loss-of-function alleles are common (~5% minor allele frequency) in African ancestry by inspecting whole-exome sequencing data from a cohort of individuals from Philadelphia in a biobank. Human genetic studies have found that loss-of-function alleles in ABCA7 in populations of European ancestry increase the risk of AD by several fold, while ABCA7 loss-of-function alleles in populations of African ancestry increase the risk of the disease by at most 80%. Based on this, we advance the hypothesis that loss of ABCA7 in African ancestry is less detrimental than in European ancestry. To test this hypothesis, we propose to delete ABCA7 in iPS cells from individuals of African and East Asian ancestry and to determine how much loss of this gene affects Aβ synthesis in iPS cell- derived neurons of these two ancestries in comparison with iPS cell-derived neurons of European ancestry. Based on the genetic studies, the prediction is that loss of ABCA7 in iPS cell-derived neurons from subjects of African ancestry will elevate Aβ production less than in iPS cell-derived neurons from European ancestry subjects. The proposed work will show whether iPS cell-derived neurons can be used to study pathophysiological differences by ancestry, conform observations from human genetics that ABCA7 plays a greater role in AD pathogenesis in European ancestry individuals and lay a foundation for further studies of the mechanisms that underlie ancestral difference in the ABCA7 effect on AD.