The Endosomal–Lysosomal Pathway Is Dysregulated by APOE4 Expression in Vivo

Possession of the ε4 allele of apolipoprotein E (<i>APOE</i>) is the major genetic risk factor for late-onset Alzheimer's disease (AD). Although numerous hypotheses have been proposed, the precise cause of this increased AD risk is not yet known. In order to gain a more comprehensive understanding of <i>APOE4</i>'s role in AD, we performed RNA-sequencing on an AD-vulnerable vs. an AD-resistant brain region from aged APOE targeted replacement mice. This transcriptomics analysis revealed a significant enrichment of genes involved in endosomal-lysosomal processing, suggesting an <i>APOE4</i>-specific endosomal-lysosomal pathway dysregulation in the brains of <i>APOE4</i> mice. Further analysis revealed clear differences in the morphology of endosomal-lysosomal compartments, including an age-dependent increase in the number and size of early endosomes in <i>APOE4</i> mice. These findings directly link the <i>APOE4</i> genotype to endosomal-lysosomal dysregulation in an <i>in vivo</i>, AD pathology-free setting, which may play a causative role in the increased incidence of AD among <i>APOE4</i> carriers.