# Proteomic and functional analysis of missense variants of APOE associated with Alzheimer disease risk

> **NIH NIH F30** · INDIANA UNIVERSITY INDIANAPOLIS · 2024 · $53,974

## Abstract

PROJECT SUMMARY
Alzheimer’s disease (AD) is a progressive neurodegenerative disease that is the most common cause of
dementia in the United States. Variants in the apolipoprotein E gene (APOE) is strongly associated with
development of AD. In the brain, APOE is mostly synthesized in the astrocytes. The primary role of APOE is to
deliver lipids and cholesterol from astrocytes to other cell types. Most humans have one of the major allele of
APOE, APOE ε2 (R176C), APOE ε3 (reference allele), and APOE ε4 (C130R). These missense variants are
associated with different levels of Alzheimer disease risks where APOE ε4 increases the risk of disease whereas
APOE ε2 decrease risk of AD. A recent analysis that genotyped over 100,000 patients showed that rare
missense variants were associated with different levels of Alzheimer disease risk. The molecular mechanism of
how variants in APOE changes astrocyte physiology that could lead to Alzheimer disease is not well known. To
attempt to understand this, our previous work adapted mass spectrometry-based thermal proteome profiling to
determine changes in protein interaction as a result of missense variants. Using yeast as simplified model, we
were able to show mutant thermal proteome profiling to resolve subcomplex level protein-protein interaction
disruptions of a protein complexes due to missense variants. To study the role of these rare missense variants
on APOE in astrocytes, we will employ an mouse primary astrocyte culture that will generate human APOE with
the specific missense variant. First, we will determine the effect of the rare missense variants on the lipoprotein
functions and astrocyte physiology. We will determine the differences between the APOE variants of uptake of
Aβ peptides, lipidation status, and the effects on the astrocyte transcriptome. Second, we will determine the
changes in protein interactions as a result in APOE variants using mutant thermal proteome profiling to detect
thermal stability changes. Taken together, these data will expand our understanding of how missense variants
change the functions of APOE and help give insight into the molecular mechanisms that result in Alzheimer
disease.

## Key facts

- **NIH application ID:** 10898779
- **Project number:** 5F30AG079580-03
- **Recipient organization:** INDIANA UNIVERSITY INDIANAPOLIS
- **Principal Investigator:** HR Sagara Wijeratne
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $53,974
- **Award type:** 5
- **Project period:** 2022-09-01 → 2026-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10898779

## Citation

> US National Institutes of Health, RePORTER application 10898779, Proteomic and functional analysis of missense variants of APOE associated with Alzheimer disease risk (5F30AG079580-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10898779. Licensed CC0.

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