Free Radical Biology & Medicine · Nov 21, 2025

APOE4 impairs Nrf2-PINK1/Parkin-dependent mitochondrial clearance through disrupted antioxidant and mitophagy signaling

By Akhter F, Akhter A, Zhu D

APOE4, the strongest genetic risk factor for sporadic Alzheimer's disease (AD), is closely associated with mitochondrial dysfunction, yet the mechanisms remain poorly defined. We identify a previously unrecognized failure of the Nrf2-PINK1/Parkin axis in APOE4 neurons that compromises mitochondrial quality control. Unlike APOE3, APOE4 neurons fail to activate PINK1/Parkin-dependent mitophagy under stress, a defect compounded by impaired Nrf2 signaling and weakened antioxidant defenses. In vivo, APOE4 mice show age-dependent collapse of this pathway, correlating with progressive mitochondrial dysfunction and disrupted mito-nuclear communication. Pharmacological activation of Nrf2 or PINK1 restores mitochondrial clearance, highlighting the axis as a druggable node. These findings provide a mechanistic link between APOE4 and mitochondrial failure, establishing the Nrf2-PINK1/Parkin pathway as a critical driver of neurodegeneration and a promising target for therapeutic intervention in AD.

doi.org/10.1016/j.freeradbiomed.2025.11.040PubMed 41275935Mechanisms