# Identifying therapeutic targets that confer synaptic resilience to Alzheimer's disease

> **NIH NIH R01** · UNIVERSITY OF ALABAMA AT BIRMINGHAM · 2021 · $1,079,457

## Abstract

Project Summary
Approximately 30%-50% of individuals who come to autopsy without dementia have high levels of Alzheimer's
disease (AD) pathology. Even in the AD population, the cellular feature most correlated with cognitive decline
is not amyloid or tau, but synaptic density. However, the molecular mechanisms behind this synaptic loss are
unclear. We have begun to explore their molecular basis through three dimensional (3D) modeling of dendritic
spines. These results show that structural remodeling of spines not only relates to cognitive decline, but
specifically relates to cognitive resilience to AD. Synaptic remodeling is highly plausible as the basis for
cognitive resilience because it is the basis for short term memory and can affect multiple cognitive processes.
This raises important questions: 1) what are the synaptic signaling pathways that drive structural remodeling of
spines to maintain cognitive abilities in resilient individuals? 2) Can we identify therapeutic targets for drug
repositioning or novel treatments to exploit these mechanisms in at risk patients? The goal of this proposal is to
build a predictive model of cognitive resilience to AD by integrating quantitative proteomics, phospho-
proteomics, 3D modeling of spines, and antemortem functional magnetic resonance imaging (fMRI) across two
brain regions from the same individuals. From computational models, candidate therapeutic protein targets will
be prioritized and rigorously validated in cellular and animal models of AD. Novel data acquired to support this
goal will measure ~12,000 proteins and ~30,000 phosphorylation sites in synapse-rich fractions from human
brains with varying degrees of resilience to AD pathology. In the same cases innovative high resolution
imaging and 3D reconstruction of dendritic architecture will measure cellular phenotypes of resilience. Systems
biology approaches will integrate our data with existing omics, including AMP-AD, and propose specific
synaptic proteins that drive resilience. These predictions will be validated in terms of human brain structure and
function by comparison to neuroimaging, acquired in the same set of humans. Top candidates for resilience
will then be screened for resilience phenotypes in cellular and animal models of disease. Human clinical,
radiologic, and pathologic data, from The Religious Orders Study and the Rush Memory and Aging Project will
be studied in combination with AMP-AD data to complete the proposed goals.

## Key facts

- **NIH application ID:** 10201513
- **Project number:** 5R01AG061800-04
- **Recipient organization:** UNIVERSITY OF ALABAMA AT BIRMINGHAM
- **Principal Investigator:** Christopher A. Gaiteri
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $1,079,457
- **Award type:** 5
- **Project period:** 2018-09-30 → 2023-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10201513

## Citation

> US National Institutes of Health, RePORTER application 10201513, Identifying therapeutic targets that confer synaptic resilience to Alzheimer's disease (5R01AG061800-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10201513. Licensed CC0.

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