Disrupted lipid homeostasis as a pathogenic mechanism in ABCA7-associated Alzheimer's disease risk.

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.