The monoaminergic systems as drivers of Alzheimer's disease pathophysiology and symptomatology

PURPOSE OF REVIEW: To summarize recent animal, postmortem and in vivo human studies examining the role of the noradrenergic and serotonergic system in the pathophysiology and symptomatology of Alzheimer's disease (AD). RECENT FINDINGS: Early in adulthood, the locus coeruleus and raphe nucleus accumulate tau, undergo morphological changes, and exhibit hyperexcitability, which contributes to the development of neuropsychiatric symptoms. 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. SUMMARY: 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 proposed monoaminergic framework intends to guide researchers into investigating the temporal dynamics between monoaminergic changes, AD pathology, and symptoms, with the ultimate goal of evaluating and developing effective precision therapeutic approaches taking into account the disease stage and symptom profile.