Introducing heterozygous humanized tau to AppNL-F/NL-F knock-in mice results in the first mouse model of Alzheimer's disease in which age and amyloid-β pathology interact to initiate neurofibrillary tau tangle pathology, not dependent on mutations in MAPT. Gradual progression from amyloid-β to tau pathology in NLFTaum/h mice opens possibilities for understanding processes precipitating clinical stages of Alzheimer's disease and development of translatable therapies to prevent the onset of tau pathology.