# Molecular Mechanisms Underlying Behavioral and Psychological Symptoms in Alzheimers Disease

> **NIH NIH R01** · NORTHWESTERN UNIVERSITY · 2021 · $692,481

## Abstract

Summary
Over 90% of Alzheimer's disease (AD) patients suffer from behavioral and psychological symptoms of
dementia (BPSD) including agitation, aggression, depression, apathy and psychosis. BPSD can present at
almost any stage of AD, and in some patients, these symptoms can even appear before dementia
develops. The severity of BPSD increases significantly with disease progression, and affects the quality of life
of both patients and their caregivers. In many patients, BPSD is the main reason for institutionalization.
However, the mechanisms underlying BPSD are not known, and there is no specific treatment strategy
available. Although BPSD presents differently in each patient, the presence of certain symptoms in a patient
make the co-occurrence of other symptoms more likely. In an ongoing collaboration with Rush Alzheimer's
Disease Center, we have developed a method for clustering the symptoms of BPSD into four domains
(affective, hyperactivity/disinhibition, psychosis and apathy). Based on these domains, we then conducted an
RNA-seq and found different gene expression profiles in AD patients with and without BPSD. This evidence
supports the notion that distinct molecular pathways may be involved in the appearance of BPSD. In this
proposal, we hypothesize that individual BPSD domains in patients with AD are due to definable perturbations
in molecular pathways and that these pathways can be analogized in AD mouse models, allowing for a causal
investigation of the relationship between specific pathway alterations and domain behaviors. We will test this
hypothesis through both human study and animal work. For the human study, 1) we will expand on our
behavioral analyses by increasing subjects for pre-mortem clinical assessments and defining BPSD trends
over time in AD patients. 2) Within each behavioral domain, we will employ RNA-seq to investigate gene
expression patterns in different brain sub-regions that are unique to each BPSD domain and the gene
expression pattern will be compared across normal, MCI and AD subjects. 3) Finally, we will identify which
pathways are most clearly associated with each of the BPSD domains using bioinformatics and biochemical
analyses. For the animal model work, 1) we will characterize how mouse behaviors analogous to human BPSD
symptoms evolve during AD-like neuropathgenesis progression 2) We will identify the most promising
molecular candidates for intervention from our RNA-seq findings using these AD/BPSD models. 3) Finally, we
will determine whether altering these pathways leads to changes in BPSD-like behavior using virally mediated
genetic manipulations (AAV9/CRISPR-Cas9). Overall, this project will establish a translational pipeline by
associating BPSD symptom domains with molecular alterations in human AD patients, and by demonstrating
that manipulations of these pathways can cause BPSD-like behaviors in transgenic mouse models of AD.
These data-driven approaches will lead to a better understanding of the mole...

## Key facts

- **NIH application ID:** 10183128
- **Project number:** 5R01AG062249-04
- **Recipient organization:** NORTHWESTERN UNIVERSITY
- **Principal Investigator:** Hongxin Dong
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $692,481
- **Award type:** 5
- **Project period:** 2018-09-30 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10183128

## Citation

> US National Institutes of Health, RePORTER application 10183128, Molecular Mechanisms Underlying Behavioral and Psychological Symptoms in Alzheimers Disease (5R01AG062249-04). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10183128. Licensed CC0.

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