# Examining the genetic regulation of A-to-I editing and mediation of Alzheimer's disease

> **NIH NIH F31** · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · 2024 · $17,938

## Abstract

Project Summary
Alzheimer’s disease (AD) is a devastating neurodegenerative disorder, affecting approximately 6 million adults
in the United States, for which there is no cure or treatments which effectively slow progression of the disease.
Genome-wide association studies (GWAS) have illuminated 75 loci associated with AD, but the causal variants
underlying the disease-associations remain to be identified, along with the genes or pathways through which
they act to regulate higher-order phenotypes. The integration of genomics with transcriptomics can inform the
influence of common genetic variation on molecular phenotypes consequential to cellular function. My lab has
shown that AD susceptibility loci are enriched for genetic variants which alter RNA levels and/or splicing, and
these variants often lie in cis-regulatory elements enriched in myeloid cells. However, causal variants or genes
remain elusive for most loci associated with AD. This proposal will contribute a valuable resource for research
seeking to describe causal variants at GWAS risk loci and connect them to altered cellular function.
Intricate pre- and post-transcriptional processing of awards vast functional diversity to RNA molecules, and
among the most abundant post-transcriptional modifications is adenosine-to-inosine (A-to-I) RNA editing. In
protein-coding regions, these base-specific changes “recode” amino acid sequences, and in non-coding
regions, A-to-I editing fine-tunes genes by influencing the splicing, stability, and subcellular localization of RNA
transcripts, along with their ability to bind micro-RNAs (miRNAs). Disrupted RNA editing activity has been
widely reported in AD patients, but whether this is a consequence of the disease, or cause is not clear. This
proposal will address the contributions of RNA editing to AD pathophysiology by testing the hypothesis that
AD-associated genetic variants modulate A-to-I editing. I will use quantitative trait loci (QTL) mapping to relate
common genetic variation to level of RNA editing at A-to-I events genome-wide in the brain and myeloid cells.
Then, I will apply advanced statistical approaches to determine whether the genetic regulators of A-to-I editing
reside in GWAS risk loci for AD. Importantly, I will implement appropriate methodology probing mediation, to
parse bona fide causal gene regulatory pathways apart from pleiotropy or spurious effects of genetic
associations. By prioritizing A-to-I editing sites which are subject to tight genetic regulation and resolving the
molecular and cellular processes they help to orchestrate, the results from this work lay critical foundation for
follow-up functional studies which can harness the power of RNA based therapeutics to develop treatments for
AD.

## Key facts

- **NIH application ID:** 11009911
- **Project number:** 5F31AG084223-02
- **Recipient organization:** ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
- **Principal Investigator:** Winston Hirschler Cuddleston
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $17,938
- **Award type:** 5
- **Project period:** 2023-09-01 → 2024-09-15

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11009911

## Citation

> US National Institutes of Health, RePORTER application 11009911, Examining the genetic regulation of A-to-I editing and mediation of Alzheimer's disease (5F31AG084223-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/11009911. Licensed CC0.

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