Dementia with Lewy Bodies (DLB) is the second most common neurocognitive pathology characterized by pathogenic deposition of α-synuclein-laden Lewy bodies within vulnerable neurons, including those of the hippocampus (HC). The strongest risk factor for sporadic Alzheimer’s disease (AD), and recently demonstrated for DLB, is the ε4 allele of apolipoprotein (APOE4) that is a major lipoprotein in the central nervous system playing a leading role in maintaining lipid homeostasis. Our group recently demonstrated that the APOE4 aggravates cognitive deficits in a mouse model of prodromal DLB – corroborating its detrimental effect on DLB development and progression. However, the mechanisms by which APOE4 exerts its role as a risk factor remain unelucidated. Epigenetic mechanisms, such as histone acetylation, are the main regulators of cell-type-specific information processing and neuroplasticity in the HC – both altered in neurodegenerative diseases. Therefore, we aimed to decipher histone acetylation landscapes and transcriptomic signatures of hippocampal astrocytes and neurons, under the influence of APOE4 and/or pathological α-synuclein fibrils mimicking DLB environment. A pronounced reduction in cholesterol biosynthesis in astrocytes was detected under the APOE4 influence alone, concomitantly with dysregulation of synaptic function and age-related epigenomic signatures in neurons. Combined with α-synuclein fibrils, APOE4 induced an increase in glial energy metabolism, while disrupting cholesterol biosynthesis and synaptic function in neurons – that displayed an epigenomic/transcriptomic signature indicative of cell identity loss. These results contribute to a better understanding of APOE4’s pathological mechanisms of action and propose a model of APOE4-driven DLB development and progression.