In Alzheimer disease (AD), tau pathology has a characteristic pattern of progression that corresponds to different disease stages and reflects neurodegenerative damage, but the region in which tau pathology first takes root has been unclear. Immunostaining of brain tissue from patients with AD first detects neurofibrillary tangles of phosphorylated tau in the locus coeruleus, but evidence suggests that this pathology is preceded by tau aggregation in the transentorhinal and entorhinal cortices (TRE–EC). A new study used a sensitive cellular biosensor assay to detect submicroscopic aggregates of tau, representing tau seeding activity, in post-mortem brain tissue from individuals with AD. The team found that tau seeding activity was evident earlier in the TRE–EC than in the locus coeruleus, suggesting that the TRE–EC and not the locus coeruleus represents the source of pathological tau seeding in AD.