Neuropsychiatric Symptoms of Alzheimer's Disease: An Anatomic-Genetic Framework for Treatment Development

Background: Despite the burden on patients and caregivers, there are no approved therapies for the neuropsychiatric symptoms of Alzheimer's disease (NPS-AD). This is likely due to an incomplete understanding of the underlying mechanisms. Objective: To review the neurobiological mechanisms of NPS-AD, including depression, psychosis, and agitation. Methods: Understanding that genetic encoding gives rise to the function of neural circuits specific to behavior, we review the genetics and neuroimaging literature to better understand the biological underpinnings of depression, psychosis, and agitation. Results: We found that mechanisms involving monoaminergic biosynthesis and function are likely key elements of NPS-AD and while current treatment approaches are in line with this, the lack of effectiveness may be due to contributions from additional mechanisms including neurodegenerative, vascular, inflammatory, and immunologic pathways. Conclusion: Within an anatomic-genetic framework, development of novel effective biological targets may engage targets within these pathways but will require a better understanding of the heterogeneity in NPS-AD.