Exfoliation glaucoma (XFG) is a clinically aggressive and genetically distinct form of glaucoma that results in neuronal death and irreversible blindness. Gene variants associate with many neurodegenerative diseases including XFG, Parkinson's disease (PD) and Alzheimer's disease (AD). Intriguingly, variants found within the same gene can either confer risk for or provide protection against all 3 of these diseases, complicating the genetic component of pathology. Unfortunately, studies that examine proteins encoded by genes having relevant variants have failed to produce therapeutic interventions that slow or stop the progression of XFG, PD, or AD in patients. This roadblock has researchers focusing on alternative pathways that may be dysregulated and potentially lead to the development of disease. Two emerging areas of research in PD and AD are the pathobiology of long noncoding RNAs and DNA methylation. This review briefly introduces the roles of long noncoding RNAs and DNA methylation in disease pathogenesis, and highlights some of the cutting edge work that has been carried out in PD and AD, along with the limited but important studies in XFG. Finally, we propose a new direction for XFG research that may explain apparently conflicting genetic data and lead to the discovery of novel dysregulated pathways that will allow for targeted therapeutic development.