# Brain and blood N-glycome profiling in Alzheimer's disease

> **NIH NIH R01** · UNIVERSITY OF FLORIDA · 2024 · $780,256

## Abstract

Project Summary
Alzheimer’s disease (AD) is a major form of dementia, affecting about 55 millions of people worldwide. Despite
substantial efforts, we still do not understand its underlying mechanisms, and thus no reliable biomarker or
effective treatment has yet been developed. Protein N-glycosylation, the enzymatic process of adding N-
glycans (i.e., sugars) to proteins, is the most common post-translational modification that regulates the function
of most proteins. Aberrant N-glycosylation has been observed in key AD-related proteins such as APP, tau,
and β-site APP-cleaving enzyme-1 (BACE1). N-glycans are diverse structured biomolecules that play crucial
roles in various biological processes including brain development and signal transduction. Altered composition
and structure of N-glycans have been associated with AD and neuroinflammation. Thus, characterizing the N-
glycome (complete repertoire of all N-glycans in a biological sample) will facilitate the discovery of novel
biomarkers and shed light on the role of N-glycosylation in AD pathology. Our preliminary data show that
baseline serum N-glycans predicts AD onset and cognitive decline over time, and altered brain N-glycans are
associated with AD pathology. However, a comprehensive landscape of the peripheral and central N-glycome
in relation to AD is still lacking, especially in large-scale human populations. The mechanisms through which
aberrant N-glycome expression contributes to AD also remain an enigma. We hypothesize that dysregulated
serum N-glycome precedes and predicts AD onset, and aberrant brain N-glycome is causally implicated in AD
pathology. Our objectives are to understand the mechanisms through which aberrant N-glycosylation affects
AD and identify circulating glycan-based markers for early prediction and risk stratification. To achieve these,
we leverage the large collection of biospecimens (antemortem serum and paired postmortem brains) in two
community-based prospective cohorts of aging and dementia (ROS and MAP). We will use the high-resolution
matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS) to
comprehensively profile the blood (serum) and brain N-glycome in relation to AD (Aims 1 and 2). The potential
causal role of aberrant N-glycome expression in AD pathology will be examined by integrative multi-omics
analyses, followed by functional validation in drosophila models of AD (Aim 3). In sum, this innovative project
leverages the wealth of deep clinical and neuropathological phenotypes as well as multi-omics data (e.g.,
glycomics, genomics, epigenomics, and transcriptomics) in the same brain cortex, and provides
unprecedented opportunities to uncover novel mechanisms underlying AD. Our proposal brings together an
exceptionally strong and unique multi-disciplinary team with complementary expertise needed to achieve our
goals. Findings of this study will significantly enhance our understanding of the mechanisms through which
a...

## Key facts

- **NIH application ID:** 10806608
- **Project number:** 1R01AG085469-01
- **Recipient organization:** UNIVERSITY OF FLORIDA
- **Principal Investigator:** Jinying Zhao
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $780,256
- **Award type:** 1
- **Project period:** 2024-05-15 → 2025-01-06

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10806608

## Citation

> US National Institutes of Health, RePORTER application 10806608, Brain and blood N-glycome profiling in Alzheimer's disease (1R01AG085469-01). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/10806608. Licensed CC0.

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