In this study, we asked why females with Alzheimer’s disease (AD) tend to experience faster cognitive decline than males with AD. We used RNA sequencing to study changes in gene expression in the nucleus accumbens, which contains a lot of cholinergic neurons. Specifically, we looked at how the expression of small RNA molecules changes in neuronal cell lines undergoing cholinergic differentiation.

We examined the brains of people with AD, and we indeed found sex-related differences in the levels of cholinergic transcripts (genetic information related to cholinergic neurons). We also found a similar sex-related effect in human neuroblastoma cells undergoing cholinergic differentiation.

Overall, our findings suggest that certain RNA molecules (called CholinotRFs) may play a role in regulating cholinergic neurons. They may be involved in the sex-specific loss of cholinergic neurons and the development of dementia in AD.

Nucleus Accumbens tRFs show larger differences than miRNAs in AD females, but not males.