Alzheimer’s Disease (AD) is a disorder characterized by cognitive decline, neurodegeneration, and accumulation of amyloid plaques and tau neurofibrillary tangles in the brain. Dysregulation of epigenetic histone modifications may lead to the expression of transcriptional programs that may play a role in disease genesis or the worsening of disease pathology. One such histone modification, acetylation of histone H3 lysine residue 27 (H3K27ac), is primarily localized to genomic enhancer regions and promotes active gene transcription. Our lab previously discovered H3K27ac to be more abundant in AD patient brain tissue compared to the brains of age-matched non-demented controls. In this thesis, I use iPSC-neurons derived from familial AD patients with an APP duplication as a model to study the functional effect of H3K27ac reduction. I found that in iPSC-neurons derived from the AD patients, homeostatic amyloid-reducing genes were upregulated compared to iPSC-neurons derived from non-demented controls. Reduction of H3K27ac decreased expression of these and other homeostatic amyloid-reducing pathway genes and increased secretion of a toxic amyloid-β species, Aβ(1-42). My findings suggest that some fraction of epigenomic H3K27ac may drive the expression of compensatory genetic programs in response to AD-associated insults, including those resulting from increased amyloid load in the context of APP duplication, and may play an important role in preventing the worsening of the disease in neurons.