Abstract: Epigenetic mechanisms regulate the chromatin structure and gene expression levels without changing the primary DNA sequence, and include DNA methylation and hydroxymethylation, post-translational modifications of histone tails and nucleosome positioning, as well as mechanisms mediated by long and short non-coding RNA molecules. These mechanisms are required for human development and cell differentiation, and are pivotal in differentiated cells for cellular functions, allowing a tight regulation of gene expression levels in response to environmental stimuli and cellular metabolic demands (Coppedè, 2021b). Particularly, the neuronal epigenome is highly sensitive to external stimuli and its function is required for learning and memory processes (Creighton et al., 2020). Several enzymes, collectively referred to as the “epigenetic machinery”, add, remove and read epigenetic marks, allowing chromatin remodeling to promote or repress gene transcription. The activity of these enzymes allows the reversibility of epigenetic marks, which is pivotal in neurons for memory formation and consolidation (Creighton et al., 2020). The epigenome is altered in the aging brain, although the factors driving these changes, their contribution to age-related memory decline, and their potential modulation with environmental interventions are still a matter of debate (Creighton et al., 2020). Furthermore, both global and gene-specific epigenetic changes are observed in blood and brain tissues of individuals with major neurodegenerative diseases, including among others Alzheimer’s disease (AD) (Coppedè, 2021a), Parkinson’s disease (PD) (Rathore et al., 2020), and amyotrophic lateral sclerosis (ALS) (Coppedè, 2020). An open question is which of these changes result from gene-environment interactions that lead to age-related declines in cognitive and motor functions, thus contributing to the onset of the disease, and which ones are consequences of the degenerative processes occurring in neurons. However, due to their reversibility, several epigenetic marks have been proposed as potential therapeutic targets to treat or delay neurodegeneration (Coppedè, 2021a). In the present article, the author provides a brief overview of the literature and its own perspective opinion on targeting the epigenome to treat neurodegeneration.