A commentary on: Locus Coeruleus Ablation Exacerbates Cognitive Deficits, Neuropathology, and Lethality in P301S Tau Transgenic Mice by Chalermpalanupap, T., Schroeder, J. P., Rorabaugh, J. M., Liles, L. C., Lah, J. J., Levey, A. I., et al. (2018). J. Neurosci. 38, 74–92. doi: 10.1523/JNEUROSCI.1483-17.2017. Alzheimer's disease (AD) is characterized by progressive neuron loss as well as the accumulation of neurofibrillary tangles, otherwise referred to as tau pathology, and β-amyloid plaques. Second to neuron loss, tau pathology is the best predictor of cognitive decline in AD. Recently, tau pathology onset in the locus coeruleus (LC) has been shown to consistently precede cortical tau pathology and increase in severity along Braak staging.