# Pyroglutamate-modified Amyloid-B protein as a marker for future cognitive decline in preclinical Alzheimer’s disease

> **NIH NIH R03** · CLEVELAND CLINIC LERNER COM-CWRU · 2020 · $160,750

## Abstract

PROJECT SUMMARY/ABSTRACT
Alzheimer's disease (AD) is the most common cause of dementia worldwide. In the US, it is the fifth leading
cause of death in people over 65 years of age. Delineating factors that predict rate of future cognitive decline
and dementia are important but are yet to be thoroughly understood.
It is now well recognized that there is substantial clinical heterogeneity among patients with AD. This
heterogeneity particularly in rate of AD progression entails a significant challenge in designing and evaluating
clinical trials for a new generation of AD therapies. Molecular factors that drive this heterogeneity are still poorly
characterized. Several post translational modifications (PTMs) of Aβ protein have been noted to impact the rate
of Aβ aggregation and its toxicity in animal models and thereby potentially impact AD progression. Studies on
animal and in vitro models of AD and brain autopsy specimens have noted pyroglutamylated Aβ PTMs as relating
to synaptic dysfunction and neuroinflammation. Among humans, the role for pyroglutamylated Aβ in impacting
future rate of cognitive decline is unknown.
The research at the foundation of this RO3 is a clinical translational study that aims to characterize the levels
pyroglutamylated Aβ at the preclinical stage of AD among humans, in relation to neuroinflammation markers,
synaptic markers and neurodegeneration markers to understand their impact on the rate of cognitive decline.
This RO3 will help us specifically evaluate the role for pyroglutamylated Aβ on future rate of cognitive decline
among normal cognition subjects at the preclinical stage of AD. We hypothesize that those subjects with higher
levels of pyroglutamylated Aβ at baseline in the CSF or plasma will have higher levels of synaptic markers, and
neuroinflammatory response contributing to faster cognitive decline over two years. By concurrently evaluating
the neuroinflammatory, synaptic and neurodegeneration related markers longitudinally, we will develop a
mechanistic model of pyroglutamylated Aβ's impact on cognition in preclinical AD. Knowledge of biological
factors that drive AD progression among humans will be critical in designing novel therapeutic strategies to
prevent cognitive decline.
This R03 will also help provide additional training and research opportunities in proteomics for Dr. Pillai to
advance his clinical research skills to address a current knowledge gap in the molecular factors impacting in AD
progression. The long-term goal of Dr. Pillai is to establish a programmatic body of research using bioinformatics
and proteomics tools to delineate the molecular factors that underpin disease progression among
neurodegenerative diseases and develop therapeutic strategies.

## Key facts

- **NIH application ID:** 9912697
- **Project number:** 5R03AG063235-02
- **Recipient organization:** CLEVELAND CLINIC LERNER COM-CWRU
- **Principal Investigator:** JAGAN AYYAPPAN PILLAI
- **Activity code:** R03 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $160,750
- **Award type:** 5
- **Project period:** 2019-04-15 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9912697

## Citation

> US National Institutes of Health, RePORTER application 9912697, Pyroglutamate-modified Amyloid-B protein as a marker for future cognitive decline in preclinical Alzheimer’s disease (5R03AG063235-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9912697. Licensed CC0.

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