Individuals with Alzheimer disease (AD) often have difficulties with spatial navigation, which depends on the entorhinal cortex (EC), but whether tau aggregates affect the EC in AD is unclear. Fu et al. studied mice expressing aggregable human tau in the hippocampal formation (EC-tau mice). Compared with controls, old EC-tau mice (aged ≥30 months) showed spatial-memory deficits in the Morris water maze and reduced grid-cell firing and periodicity. Moreover, tau aggregation and cell death in old EC-tau mice specifically affected excitatory, but not inhibitory, neurons in the medial EC. Thus, tau aggregates may impair spatial memory in AD by affecting EC network activity.