VPS26B encodes a component of the retromer cargo-selective complex (CSC) that mediates retrograde transport of transmembrane proteins from endosomes to prevent their lysosomal degradation 1. VPS26B forms a distinct retromer complex from its paralog VPS26A, with VPS26B-retromer showing different cargo specificity and subcellular localization patterns 2. Unlike VPS26A-retromer, VPS26B-retromer does not interact with the cation-independent mannose 6-phosphate receptor (CI-M6PR) and shows prolonged association with maturing endosomes 2. The protein is particularly enriched in neurons and plays a critical role in endosomal recycling, with the trans-entorhinal cortex being most vulnerable to VPS26B depletion 3. VPS26B regulates trafficking of specific cargo proteins including PAR-2 receptor resensitization and GLUT1 recycling 45. Disease relevance is significant, as VPS26B levels are reduced in Down syndrome and Alzheimer's disease, correlating inversely with Aβ levels 67. The reduction appears dependent on APP gene dosage and can be prevented by γ-secretase modulator treatment, suggesting a causal role for amyloid peptides in retromer dysfunction 7. These findings establish VPS26B as a potential therapeutic target for neurodegenerative diseases.