TMEM50B (transmembrane protein 50B) is a conserved transmembrane protein located on chromosome 21 with demonstrated relevance to neurological diseases. The protein localizes to the endoplasmic reticulum and plasma membrane, with putative involvement in protein binding and late endosome-to-vacuole transport via multivesicular body sorting [GO annotations]. TMEM50B exhibits extremely high sequence conservation across mammalian species 1, suggesting functional importance. In Down syndrome, TMEM50B is upregulated approximately two-fold compared to normal samples and was identified as a differentially expressed gene in the Ts1Cje mouse model of Down syndrome, with expression changes documented across cerebral cortex, cerebellum, and hippocampus during postnatal brain development 23. Notably, TMEM50B was identified as one of nine replicated female-specific gene associations in Alzheimer's disease, specifically correlating with longitudinal cognitive trajectory in a single-nucleus transcriptomic analysis of 2.84 million nuclei from the dorsolateral prefrontal cortex 4. These associations suggest TMEM50B may contribute to sex-specific neuropathological mechanisms in neurodegeneration. However, the precise molecular mechanism by which TMEM50B influences cognitive outcomes or neurological disease pathology remains to be elucidated.