Epigenetic mechanisms, including histone acetylation, play a key role in learning and memory, with recent evidence of a role in neuronal function in Alzheimer’s disease and Related Dementia (ADRD). Acetyl-CoA sythetase 2 (ACSS2) is central to epigenetics and gene regulation, particularly in neurons, due to their unique metabolic demands and their postmitotic state. ACSS2 can be directly recruited to the nucleus to locally supply acetyl-CoA, and to directly fuel histone acetyltransferases. This gene regulatory mechanism presents a promising avenue for targeted therapeutic interventions in neurodegenerative diseases. Building upon our prior discovery that systemic ACSS2 deletion in mouse impairs memory and reduces immediate early gene expression, we explored whether increasing levels of ACSS2 to boost chromatin processes could protect neurons against disease and age-associated cognitive decline. Given the role of tau in ADRD, we used primary hippocampal neurons that mimic the sporadic development of tau pathology, and the PS19 transgenic mouse model for tau-induced memory decline. We show that ACSS2 upregulation mitigates tau-induced transcriptional alterations, enhances neuronal resilience against tau pathology, improves long-term potentiation, and ameliorates memory deficits. Expanding upon our findings, we investigated ACSS2-dependent epigenetic modifications in aged mice. Our results reveal that increasing histone acetylation through ACSS2 upregulation also improves age-associated memory decline. These findings show that increasing the level of ACSS2 is highly effective in countering age and tau-induced transcriptomic changes, preserving elevated levels of synaptic genes, and thereby safeguards synaptic integrity over time. Our results highlight ACSS2 as a key player in the epigenetic regulation of cognitive aging and ADRD, thus opening exciting prospects for targeted therapeutic strategies aimed at enhancing brain resilience and function.