A Proteomic and Genomic Approach to Understanding Neuropsychiatric Symptoms in Alzheimer's Disease

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Alzheimer’s disease is a neurodegenerative disorder characterized by protein aggregation and cognitive decline. Patients with Alzheimer’s disease experience neuropsychiatric symptoms including hallucinations and delusions, which are also characteristic of schizophrenia. Evidence suggests that female patients with Alzheimer’s disease have a more insidious onset of illness, and many have more neuropsychiatric diagnoses. We recently discovered that protein insolubility is increased in a subset of postmortem brains from patients with schizophrenia. While schizophrenia is not a neurodegenerative disorder, and does not exhibit widespread neuronal loss, our evidence suggests that, as in neurodegenerative disorders, protein aggregation may be present in schizophrenia. This could alter the functioning of neurons and contribute to pathogenesis. Furthermore, since Alzheimer’s disease can present with psychiatric symptoms, and these symptoms may occur prior to cognitive decline, some of the cellular processes that cause proteins to aggregate in Alzheimer’s disease may be comparable to those in schizophrenia. Intriguingly, our data suggest that aggregation may occur more often in female compared to male patients with schizophrenia. We hypothesize that the overlapping proteomic changes associated with protein aggregation in schizophrenia and Alzheimer’s disease will implicate genes and proteins, and thus specific cellular processes, associated with the sex differences in neuropsychiatric symptoms and psychosis observed in Alzheimer’s disease. In order to test this hypothesis, we proposed to analyze proteomic data using a bioinformatics approach in order to characterize the cellular processes associated with aggregated proteins present in schizophrenia versus control postmortem brains (Aim 1). We will then analyze proteomic data using a bioinformatics approach in order to identify potentially overlapping aggregated proteins present in schizophrenia versus Alzheimer’s postmortem brain with psychosis (Aim 2). Finally, we will use a genomics approach to determine whether the genes from the set of overlapping proteins identified in Aim 2 are enriched in genome wide association studies for neuropsychiatric symptoms related to Alzheimer’s disease. We will also perform a sub analysis to determine whether this enrichment is more predominant in women than men (Aim 3). This proposal may provide evidence that the mechanisms responsible for aggregation in schizophrenia contribute to the neuropsychiatric symptoms that occur in Alzheimer’s disease, particularly those observed in women. Exploration into this subject could elucidate pathogenesis and ultimately provide therapeutic targets. Further, this research plan is complemented by an integrated training plan that focuses on training in 1) analytical biostatistics and computational methods, 2) quantitative proteomic and genomic analysis and 3) interpretation of proteomic and genomic data and its biological context, including the clinical and neurobiological aspects of AD, all of which will facilitate the candidate’s development into an independent investigator.