Disrupted Lipid Homeostasis as a Pathogenic Mechanism in ABCA7-Associated Alzheimers Disease Risk

Abstract

INTRODUCTIONABCA7 (ATP-binding cassette sub-family A member 7) encodes a lipid transporter linked to Alzheimers disease (AD). While common variants confer modest risk in Europeans, a 44-base pair deletion (rs142076058; p.Arg578Alafs) is a strong risk factor in African Americans (AA). Despite this, the biological consequences of this ancestry-specific variant are not well understood. METHODSWe expressed the truncated ABCA7 protein in HEK and HepG2 cells to assess localization and lipid metabolism. Additionally, induced pluripotent stem cell (iPSC)-derived neurons carrying the deletion were compared with isogenic controls. RESULTSThe truncated ABCA7 localized to the plasma membrane similarly to wild type but induced significant lipid droplet accumulation in HepG2 cells and iPSC-derived neurons. DISCUSSIONThese findings show that the AA-specific ABCA7 deletion disrupts lipid regulation despite normal localization, suggesting a mechanistic link between impaired lipid homeostasis and increased AD risk. This work underscores the importance of ancestry-specific studies in AD research. HighlightsO_LITruncated ABCA7 protein remains stable and correctly localizes to the plasma membrane in HEK293T cells. C_LIO_LITruncated ABCA7 disrupts lipid droplet regulation in HepG2 cells. C_LIO_LIABCA7 shows the highest expression in neurons among brain cell types. C_LIO_LIABCA7 truncation impairs lipid metabolism in neurons. C_LI