Cross-Species and Cell-Type-Specific H3K27ac Dynamics Link Brain Aging to Alzheimer’s Disease Genes

Active H3K27ac marks are dynamically remodelled during brain aging, but their cell-type-specific regulatory roles remain unclear. We integrated genome-wide H3K27ac profiles and transcriptomes from aging Drosophila heads, mouse NeuN+ forebrain neurons, and human NeuN+/NeuN− frontal cortex cells. In Drosophila, age-gained differential (Δ) H3K4me1 and H3K27ac peaks were associated with RNA processing and immune response genes, respectively, suggesting distinct regulatory programs. Despite limited biological replicates, mouse analyses revealed a strong association between promoter-associated ΔH3K27ac and synaptic gene expression in young neurons. Age-related gene-body H3K27ac loss coincided with increased expression of genes involved in GTPase signalling and vesicular transport. In humans (n = 29), NeuN− cells exhibited more age-associated ΔH3K27ac alterations than NeuN+ cells. Genes associated with age-gained peaks were enriched for gliogenesis and amyloid precursor protein metabolic processes, while age-related transcriptional changes associated positively with super-enhancer activity. Comparison with pan-tissue aging signatures revealed shared and cell-type-specific age-related ΔH3K27ac patterns in NeuN+ and NeuN− cells. Integrative analyses showed that age-gained ΔH3K27ac peaks in NeuN− cells overlapped with AD-associated ΔH3K27ac peaks, differentially expressed AD genes, and AD GWAS-linked variants, including those mapped to BIN1 and CR1. These findings highlight extensive H3K27ac remodelling in aging NeuN− cells and its convergence with AD-associated molecular alterations.