NOMe-Seq profiles both nucleosome occupancy and endogenous CpG methylation. Using rare samples, such as brain neuronal subpopulations, means less cells are available for library construction, therefore methods which allow profiling of multiple epigenetic marks from the same library are important in characterising a more comprehensive epigenetic profile. We performed NOMe-Seq on human neuronal cells with differing Alzheimer's disease (AD) pathology. In contrast to the majority of NOMe-Seq data, in these experiments we have multiple replicates (n=6) for each condition, which have lower coverage than a typical n=1 experiment, meaning the current bioinformatic methods for nucleosome depleted region (NDR) detection in single samples are not appropriate. We therefore developed statistical methods for differential nucleosome occupancy between conditions, utilising the larger number of replicates sequenced. Our methods show enrichment of differentially occupied regions near neuronal genes in our AD samples. Furthermore, these methods allow for simultaneous differential nucleosome occupancy and differential methylation from the same libraries, which has never been performed before.