# Critical assessment of DNA adenine methylation in brain cells from healthy aging and Alzheimer's disease

> **NIH NIH R56** · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · 2021 · $745,674

## Abstract

PROJECT SUMMARY/ABSTRACT
DNA methylation contributes to epigenetic regulation of many important biological processes. The prevailing
dogma is that DNA methylation almost exclusively occurs at the fifth position of cytosine (5mC) in eukaryotes.
This dogma has been revised in the past five years as multiple studies reported the existence of N6-
methyladenine (6mA) across eukaryotes including the mouse and human genome. A few studies have found
evidence that suggests the diverse functions 6mA plays in mammals. Some studies have also reported
increased 6mA level in certain neuronal cells and upon social stress, suggesting 6mA may play important roles
in health and diseases. However, several studies have challenged the presence of 6mA in mammalian
genomes, highlighting multiple sources of confounding factors. The active debate has created unusual
confusions in the epigenetic community. Yet, tens of studies continued to report new discoveries about 6mA in
the human genome including some papers at high-profile journals. A few ongoing research studies have set
out to examine the functional roles of 6mA in brain cells and brain disorders, especially in Alzheimer’s disease.
To unambiguously assess the abundance and prevalence of 6mA in the human genome, it is imperative to
employ a reliable and sensitive 6mA mapping method. However, past and ongoing studies mostly employ
antibody-based methods, which are associated with non-specificity. Although Single Molecule Real-Time
sequencing (SMRT-seq) has been widely used to map 6mA at base resolution in bacteria, recent work by us
and others have found that existing methods are not sensitive enough for eukaryotic genomes with low 6mA
abundance. To address this fundamental technological gap, we will build on our >10-yr experience in SMRT-
seq to develop a new method for sensitive 6mA detection, and take a neutral perspective to critically examine
6mA in the human genome and in brain tissues from patients with Alzheimer’s disease (AD), Primary age-
related tauopathy (PART, another type of dementia) and controls. This project is significant and very timely
because (1) if the novel method supports the existence of 6mA in the human genome, it will provide ongoing
and future studies with a much-needed tool to detect 6mA in certain cell types and Alzheimer’s diseases; (2) if
the novel method does not support a significant level of 6mA as reported, it will serve as a much-needed direct
evidence to clarify the current debate.

## Key facts

- **NIH application ID:** 10365337
- **Project number:** 1R56AG071291-01A1
- **Recipient organization:** ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
- **Principal Investigator:** Kristen Jennifer Brennand
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $745,674
- **Award type:** 1
- **Project period:** 2021-07-01 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10365337

## Citation

> US National Institutes of Health, RePORTER application 10365337, Critical assessment of DNA adenine methylation in brain cells from healthy aging and Alzheimer's disease (1R56AG071291-01A1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10365337. Licensed CC0.

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