Background Sex differences in Alzheimers disease (AD) have been documented for decades, and many sex-specific molecular contributors to AD have been discovered through bulk omics analysis of brain tissues. RNA sequencing (RNAseq) at single cell resolution provides an opportunity to characterize transcript associations with AD in a cell type-specific matter. Here, we investigated sex-specific gene expression associations with neuropathology and cognitive manifestation of AD (endophenotypes) leveraging a large single-nucleus transcriptomic dataset consisting of 1.64 million nuclei from dorsolateral prefrontal cortex (DLPFC) tissue of 424 unique donors from the Religious Orders Study and Memory and Aging Project (ROS/MAP; AD Knowledge Portal syn2580853). Methods ROS/MAP single-nucleus RNAseq data (snRNA-seq) were processed through a rigorous pipeline. In total, eight major cell types from DLPFC were identified from this dataset. We first performed sex-stratified and sex-interaction associ

Enhancer RNAs (eRNAs) are transcribed by RNA polymerase II during enhancer activation but are typically rapidly degraded in the nucleus. During states of reduced RNA surveillance, however, eRNAs and other similar “noncoding” RNAs, including for example upstream antisense RNAs, are stabilized, and some are exported to the cytoplasm and can even be found on polysomes. Here, we report unexpectedly that ~12% of human intergenic eRNAs contain long open reading frames (>300 nts), many of which can be actively translated, as determined by ribosome profiling, and produce proteins that accumulate in cells, as shown by mass spectrometry (MS) data. Focusing on the largest of the encoded proteins, which we designate as eORFs, and which can be up to ~45 KDa, we found remarkably that most are highly basic, with pIs >11.5. This unusual chemistry reflects a striking overabundance of arginine residues, and occurs despite a relative paucity of lysines. Exogenous expression of the ten largest eORFs revea