As cortical AD pathology increases, these nuclei become hypoactive, but elevated neurotransmitter levels persist in the cortex, presumably driving amyloid-related hyperexcitability and contributing to tau spreading and cognitive decline.<h4>Summary</h4>The pathologic changes occurring within these monoaminergic systems temporally align with the observation that neuropsychiatric symptoms precede cognitive changes in AD, indicating that these systems link the earliest pathobiology of the disease to the evolution of the symptoms. The gene discussed is MAPT; the disease is Alzheimer disease.