Disrupted Lipid Homeostasis as a Pathogenic Mechanism in ABCA7-Associated Alzheimer’s Disease Risk

bioRxiv, September 2025

40950052

Younji Nam, Brooke A. DeRosa, Aura M. Ramirez, Biniyam A. Ayele, Patrice Whitehead-Gay, Larry D. Adams, Charles G. Golightly, Takiyah D. Starks, Mayra Juliana Laverde-Paz, Holly N. Cukier, Rufus Akinyemi, Fred Sarfo, Albert Akpalu, Michael L. Cuccaro, Scott M. Williams, Allison Caban-Holt, Christiane Reitz, Jonathan L. Haines, Goldie S. Byrd, Farid Rajabli, Derek M. Dykxhoorn, Juan I. Young, Jeffery M. Vance, Margaret A. Pericak-Vance

ABCA7 (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. We 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. The truncated ABCA7 localized to the plasma membrane similarly to wild type but induced significant lipid droplet accumulation in HepG2 cells and iPSC-derived neurons. These 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.