The global epidemic of Alzheimer disease (AD) is worsening, and no approved treatment can revert or arrest progression of this disease. AD pathology is characterized by the accumulation of amyloid-β (Aβ) plaques and tau neurofibrillary tangles in the brain. Genetic data, as well as autopsy and neuroimaging studies in patients with AD, indicate that Aβ plaque deposition precedes cortical tau pathology. Because Aβ accumulation has been considered the initial insult that drives both the accumulation of tau pathology and tau-mediated neurodegeneration in AD, the development of AD therapeutics has focused mostly on removing Aβ from the brain. However, striking preclinical evidence from AD mouse models and patient-derived human induced pluripotent stem cell models indicates that tau pathology can progress independently of Aβ accumulation and arises downstream of genetic risk factors for AD and aberrant metabolic pathways. This Review outlines novel insights from preclinical research that implicate apolipoprotein E, the endocytic system, cholesterol metabolism and microglial activation as Aβ-independent regulators of tau pathology. These factors are discussed in the context of emerging findings from clinical pathology, functional neuroimaging and other approaches in humans. Finally, we discuss the implications of these new insights for current Aβ-targeted strategies and highlight the emergence of novel therapeutic strategies that target processes upstream of both Aβ and tau.