In the past decade, an increasing number of studies have been focusing on identifying Alzheimer’s disease (AD)-related epigenetic modifications, both in humans and mouse models. Recently, it has been shown that late-stage AD human samples show alterations in histone modifications, chromatin compartmentalisation, and chromatin structural protein localisation (Xiong et al., Cell, 2023). These changes collectively result in epigenome erosion. However, the mechanisms and the role of chromatin structural proteins underpinning this event remain unclear. Likewise, it remains uncertain whether cognitive enhancement drugs, like HDAC inhibitors, can recover such changes, whether their effect on 3D chromatin structure is cell type specific, and whether their effectiveness varies with the AD stage of administration. To address these knowledge gaps, we employ APP/PS1 transgenic mice and wild-type (WT) C57Bl/6 mice at pre-symptomatic (4 months of age), early symptomatic (9 months of age) and late symptomatic (14 months of age). We investigate the effects of the HDAC inhibitor CI-994 on the epigenetic landscape, at the single-cell level, across all time points. Pairing CI-994 with Morris water maze, we found that CI-994 impact on learning strengthens with AD severity. Ongoing investigations focus on accessibility changes post CI-994 injection. In the future we aim to provide important and insightful information on the influence of 3D chromatin conformation on AD development and on the effects of CI-994 administration on these changes. Lastly, using single-cell approaches will allow us to clarify which specific cell subtypes play a more significant role in AD-related alterations in the epigenetic landscape.