Appropriate histone acetylation homeostasis is critical for neural health and function and is maintained by the antagonistic activity of histone acetlytransferase (HAT) and histone deacetylases (HDAC). Disruption of this fine tuned epigenetic balance involving reduced levels of histone acetylation in the brain causes significant cognitive deficits that are a debilitating hallmark of most neurodegenerative disorders, including Alzheimer’s disease (AD). Nevertheless, the HATS that generate these neuroepigenetic marks and their mechanisms of action remain largely unclear. We recently made the exciting discovery that Tip60 is critical for cognitive processes based on its role in neural epigenetic cognition gene control and remarkably, promotes neuroprotection for multiple cognitive neural circuits impaired in the brain during early AD associated neurodegenerative progression. Our findings support a model by which Tip60 promotes neuroprotection by epigenetically reprogramming gene sets that together protect and/or promote cognitive function. To test this model, we performed a gene expression analysis screen on 15 Tip60 cognition-linked target genes that have human homologs. Notably, we found that while expression for all 15 genes was repressed in the AD associated APP neurodegenerative fly brain, expression of 10 of these genes was restored by increasing Tip60 levels in the brain. We next tested possible epigenetic-based mechanisms for Tip60 transcriptional rescue under APP neurodegenerative conditions. Recent compelling studies show reduced histone acetylation levels and enhanced repressor HDAC2 activity in a variety of AD models and in the human AD brain. Thus, we selected 5 of the Tip60 rescued cognition genes and assessed levels of histone acetylation, Tip60 and HDAC2 enrichment using ChIP analysis with Abs to Tip60, Rpd3 (HDAC2), and acetylation marks at histone H4K5,12,and 16 in fly brains expressing APP versus APP and excess Tip60 levels. We found that all histone acetylation marks were reduced in the APP neurodegenerative fly brain and restored by increasing Tip60 levels. Conversely, repressor HDAC2 binding enrichment at these 5 cognition genes was enhanced in the APP fly brain and remarkably, significantly reduced in 3 out of the 5 genes tested upon increased Tip60 levels. Together, our results support a model by which increasing Tip60 in the neurodegenerative fly brain restores Tip60 binding and acetylation levels at cognition gene loci by displacing inappropriate HDAC2 binding, thus activating Tip60 cognitive gene expression to promote neuroprotection.