# Understanding the molecular mechanisms of Depression and Psychological Well-being in Alzheimer's disease

> **NIH NIH R01** · EMORY UNIVERSITY · 2020 · $799,093

## Abstract

Psychological well-being (PWB) and depression are important factors that modify risk for Alzheimer's
disease (AD), a disorder of progressive erosion of memory and cognition. Specifically, depression is
associated with increased risk for AD dementia while PWB with decreased risk for AD after controlling for
depression. Molecular mechanisms underlying these important associations, however, are not known and are
the focus of this proposal. Based on emerging evidence from our studies and others', we hypothesize that
altered expression of key microRNAs (miRNAs) contribute to the effects of depression and PWB on AD risk.
 To test this hypothesis we propose to study a unique dataset of 850 human postmortem brains from the
Rush Memory and Aging Project (MAP). This prospective longitudinal study annually collects data on
depression, PWB, cognition, physical health, and dementia, and genomic, transcriptomic, and proteomic data
from the dorsolateral prefrontal cortex (dPFC). We propose a 2-stage genetic study to identify key miRNAs,
transcripts, and proteins associated with depression, and separately with PWB, and examine how they relate
to cognitive change, AD dementia, and dementia-related pathologies. Our discovery dataset will be the 600
MAP samples and replication set will be 250 MAP samples, followed by a joint analysis of all 850.
 In Aim 1 we propose to identify miRNAs specific to depression and PWB, respectively, through
genome-wide miRNA expression analyses. We will then determine how these miRNAs are associated with AD
phenotypes (i.e. rate of cognitive decline, clinical diagnosis of dementia, and dementia-related pathologies).
We anticipate identifying miRNAs significantly associated with both depression and AD (referred to as Dep-AD-
miRNAs), and to both PWB and AD (PWB-AD-miRNAs). In Aim 2, we examine transcript levels of the targets
of the Dep-AD-miRNAs and PWB-AD-miRNAs in AD phenotypes. We hypothesize that mRNA levels of these
targets will be associated with AD phenotypes. Additionally, we will perform co-expression network analysis on
existing transcriptomes to identify expression modules and key expression drivers for depression and PWB,
separately. We will then test if these key expression drivers are associated with AD phenotypes. In Aim 3, we
will examine protein levels of the downstream targets of the Dep-AD-miRNAs and PWB-AD-miRNAs in AD
phenotypes. We also test whether protein levels of the significant transcripts from Aim 2 are associated with
AD phenotypes. Lastly, we will perform network analysis on existing global proteomes to identify novel
proteomic drivers for depression and PWB, respectively, and examine their association with AD phenotypes.
 This project can potentially identify important molecular contributors of AD dementia that might not be
apparent through other approaches, leading to new insights into mechanisms and treatment targets for AD and
thereby have an important and sustained impact on public health.

## Key facts

- **NIH application ID:** 9925771
- **Project number:** 5R01AG056533-04
- **Recipient organization:** EMORY UNIVERSITY
- **Principal Investigator:** Aliza Pham Wingo
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $799,093
- **Award type:** 5
- **Project period:** 2017-09-15 → 2022-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9925771

## Citation

> US National Institutes of Health, RePORTER application 9925771, Understanding the molecular mechanisms of Depression and Psychological Well-being in Alzheimer's disease (5R01AG056533-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9925771. Licensed CC0.

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