# Redefining the Role of APOE RNA Transcripts in Alzheimer's Disease

> **NIH VA I01** · VA PUGET SOUND HEALTHCARE SYSTEM · 2024 · —

## Abstract

The apolipoprotein E gene (APOE) has three genetic variants (i.e., ε2, ε3, and ε4), and the ε4 variant of the
APOE is the strongest genetic risk factor for Alzheimer's disease (AD). This means that APOE plays a major
role in the development of AD. The expression levels of APOE gene products (mRNA and protein) are potential
candidates that may partially explain APOE's effects in AD. But studies on APOE expression in AD have always
yielded conflicting data, and there is no consensus on whether ε4 carriers produce higher or a lower APOE
mRNA/protein. Such conflicting results have significantly obscured interpretation of APOE's expression role in
AD. Clearly, gaps exist between APOE's expression, the ε2/ε3/ε4 alleles, and AD status. There is a need for
better understanding their relationship. In our preliminary study, we have found that only a fraction of APOE
mRNA extends the full length of the gene; that is, the majority of mRNAs are prematurely terminated and cannot
produce functional apoE proteins. We have also detected the presence of novel circular RNAs in APOE RNA
pools. These data suggest that APOE's RNA transcription is complex and may pose more biological
consequences than previously thought; and that past APOE mRNA expression studies may have been flawed
for not measuring the true functional full-length mRNA. Deciphering the interplay between various APOE RNA
transcripts, the production of full-length mRNA, and the ε2/ε3/ε4 alleles will lead us to better understand the
effects of APOE expression in AD. In this study, we hypothesize that only a fraction of APOE mRNA extend the
full length of the gene to produce apoE protein; the ε2/ε3/ε4 alleles differentially modulate the production of these
functional full-length mRNAs, thereby adding diverse effects to AD risk. Our long-term goal is to fully understand
gene regulation of APOE and to use this knowledge to develop strategies for AD prevention and/or intervention.
Our short-term goal is to clarify the relationship between APOE RNAs transcription, the ε2/ε3/ε4 variants, and
AD risk and to understand the molecular mechanisms that regulate APOE RNAs production. We have designed
three specific aims for the study. Aim 1 will investigate APOE RNAs and correlate their expression levels with
the ε2/ε3/ε4 allele variants, and AD status in human postmortem brain. Aim 2 will characterize the epigenetic
mechanisms that modulate the APOE RNAs transcription in human cell lines. Aim 3 will investigate the function,
biogenesis, and distribution of the newly discovered APOE circular RNA in human cell lines and body fluid. Our
work will not diminish the role of apoE protein; instead, it will dissect the contributions of APOE RNA from apoE
protein to complement APOE gene's comprehensive effects in AD.

## Key facts

- **NIH application ID:** 10830239
- **Project number:** 5I01BX000933-13
- **Recipient organization:** VA PUGET SOUND HEALTHCARE SYSTEM
- **Principal Investigator:** CHANG-EN YU
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2024
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2011-01-01 → 2024-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10830239

## Citation

> US National Institutes of Health, RePORTER application 10830239, Redefining the Role of APOE RNA Transcripts in Alzheimer's Disease (5I01BX000933-13). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10830239. Licensed CC0.

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