Alzheimer's & dementia : the journal of the Alzheimer's Association · 2026
Disrupted lipid homeostasis as a pathogenic mechanism in ABCA7-associated Alzheimer's disease risk.
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Nam Younji, DeRosa Brooke A, Ramirez Aura M, Ayele Biniyam A, Whitehead-Gay Patrice, Adams Larry D, Golightly Charles G, Starks Takiyah D, Laverde-Paz Mayra Juliana, Cukier Holly N, Akinyemi Rufus, Sarfo Fred, Akpalu Albert, Cuccaro Michael L, Williams Scott M, Caban-Holt Allison, Reitz Christiane, Haines Jonathan L, Byrd Goldie S, Rajabli Farid, Dykxhoorn Derek M, Young Juan I, Vance Jeffery M, Pericak-Vance Margaret A
Аннотация
INTRODUCTION: ABCA7 (ATP binding cassette subfamily A member 7) encodes a lipid transporter associated with increasing risk for Alzheimer's disease (AD). A 44-base pair deletion in ABCA7 (rs142076058; p.Arg578Alafs) is a strong risk factor in individuals of African ancestry (AA). However, the biological consequences of this deletion are poorly understood.
METHODS: We expressed the truncated ABCA7 protein in HEK and HepG2 cells to assess cellular localization and impact on lipid metabolism, respectively. Additionally, induced pluripotent stem cell (iPSC)-derived neurons carrying the deletion were functionally assessed compared to isogenic controls.
RESULTS: Truncated ABCA7 localized to endoplasmic reticulum and plasma membranes similarly to the wild type in HEK cells but induced significant lipid droplet accumulation in HepG2 cells and iPSC-derived neurons while reducing mitochondrial membrane potential in iPSC-derived neurons.
DISCUSSION: These findings show that the AA-specific ABCA7 deletion disrupts lipid and mitochondrial homeostasis, supporting a mechanistic link between the ABCA7 deletion and increased AD risk.
METHODS: We expressed the truncated ABCA7 protein in HEK and HepG2 cells to assess cellular localization and impact on lipid metabolism, respectively. Additionally, induced pluripotent stem cell (iPSC)-derived neurons carrying the deletion were functionally assessed compared to isogenic controls.
RESULTS: Truncated ABCA7 localized to endoplasmic reticulum and plasma membranes similarly to the wild type in HEK cells but induced significant lipid droplet accumulation in HepG2 cells and iPSC-derived neurons while reducing mitochondrial membrane potential in iPSC-derived neurons.
DISCUSSION: These findings show that the AA-specific ABCA7 deletion disrupts lipid and mitochondrial homeostasis, supporting a mechanistic link between the ABCA7 deletion and increased AD risk.