Steps Towards Developing Effective Treatments for Neuropsychiatric Disturbances in Alzheimer’s Disease: Insights From Preclinical Models, Clinical Data, and Future Directions

Alzheimer’s disease (AD) is the most common form of dementia worldwide. It is mostly known for its devastating effect on memory and learning but behavioral alterations commonly known as neuropsychiatric disturbances (NPDs) are also characteristics of the disease. These include apathy, depression-like behavior, and sleep disturbances, and they all contribute to an increased caregiver burden and earlier institutionalization. The interaction between NPDs and AD pathology is not well understood, but the consensus is that they contribute to disease progression and faster decline. Consequently, recognizing and treating NPDs might improve AD pathology and increase the quality of life for both patients and caregivers. In this review article, we examine previous and current literature on apathy, depressive symptoms, and sleep disturbances in AD patients and preclinical AD mechanistic models. We hypothesize that tau accumulation, beta-amyloid (Aβ) aggregation, neuroinflammation, mitochondrial damage, and loss of the locus coeruleus (LC)-norepinephrine (NE) system all collectively impact the development of NPDs and contribute synergistically to AD pathology. Targeting more than one of these processes might provide the most optimal strategy for treating NPDs and AD. The development of such clinical approaches would be preceded by preclinical studies, for which robust and reliable mechanistic models of NPD-like behavior are needed. Thus, developing effective preclinical research models represents an important step towards a better understanding of NPDs in AD.