Beyond memory impairment: the complex phenotypic landscape of Alzheimer's disease

Abstract

Neuropsychiatric symptoms (NPSs) in Alzheimer's disease (AD) constitute multifaceted behavioral manifestations that reflect processes of emotional regulation, thinking, and social behavior. They are as prevalent in AD as cognitive impairment and develop independently during the progression of neurodegeneration. As studying NPSs in AD is clinically challenging, most AD research to date has focused on cognitive decline. In this opinion article we summarize emerging literature on the prevalence, time course, and the underlying genetic, molecular, and pathological mechanisms related to NPSs in AD. Overall, we propose that NPSs constitute a cluster of core symptoms in AD, and understanding their neurobiology can lead to a more holistic approach to AD research, paving the way for more accurate diagnostic tests and personalized treatments embracing the goals of precision medicine.

Keywords: Alzheimer’s disease; multiomics; neuroimaging; neuropsychiatric symptoms; precision medicine.

Figure 1.. Summary of the genetic and molecular mechanisms shared between AD and SMI.

A. Shared genetic architecture between AD and MDD, and between AD and psychosis. B. Shared gene expression signatures in the superior temporal gyrus (STG), the dentate gyrus and the hippocampus implicate the autophagy regulation system in AD and schizophrenia (SCZ); shared gene expression signatures implicate microglial response in AD and BD; shared gene expression signatures implicate immune response and endocytosis regulation in AD and MDD. C. Shared causal proteins between AD and schizophrenia (ACE, ADAM10, CCDC6, DOC2A) and between AD and BD (CCDC6 and MTSS1L). D. Shared protein-protein interactions between AD causal proteins (STX6, LACTB, CCDC6) and SMI causal proteins. Figure was created with Biorender (www.biorender.com).