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

> **NIH NIH K01** · JOHNS HOPKINS UNIVERSITY · 2021 · $129,735

## Abstract

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, includin...

## Key facts

- **NIH application ID:** 10126150
- **Project number:** 1K01AG066863-01A1
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** Leslie Giselle Nucifora
- **Activity code:** K01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $129,735
- **Award type:** 1
- **Project period:** 2021-09-01 → 2026-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10126150

## Citation

> US National Institutes of Health, RePORTER application 10126150, A Proteomic and Genomic Approach to Understanding Neuropsychiatric Symptoms in Alzheimer's Disease (1K01AG066863-01A1). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10126150. Licensed CC0.

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