RAN and neurodegenerative disease: Specifically, we demonstrated that brain glucose hypometabolism—which is a consistently observed phenomenon that occurs years before symptom onset in C9orf72 patients but also in other neurodegenerative diseases (Cunnane et al, 2020; De Vocht et al, 2020; Popuri et al, 2021)—can act as a modifier of RAN translation and ultimately prime and exacerbate disease phenotypes, both in in vitro and in vivo models of disease.