Disruption of large-scale brain networks accompanies normal aging and is implicated in cognitive decline even in absence of neurodegenerative disease.1 Changes in episodic memory have been associated with changes in the functional connectivity of the default mode network (DMN), even after adjusting for atrophy, in cognitively normal older adults.2 Functional alteration of the DMN has been used to predict cortical thinning independently of temporal tau burden in preclinical Alzheimer’s disease.3 Among large-scale brain networks, the DMN is particularly relevant in Alzheimer’s disease. The gene discussed is MAPT; the disease is early-onset autosomal dominant Alzheimer disease.