# Rates and mechanisms of age-related somatic mutation in normal and Alzheimer brain

> **NIH NIH R01** · BOSTON CHILDREN'S HOSPITAL · 2022 · $865,985

## Abstract

Aging in humans is associated with a host of brain diseases, including tumors of glial progenitor cells
and degeneration of neuronal cells. However, the mechanisms by which age and disease risk interact are
poorly understood. Recent studies from our group have shown that somatic single nucleotide variants (sSNV)
accumulate even in nondividing neurons in the human cortex, resulting in thousands of sSNV per neuronal
genome by old age. Further, the patterns of sSNV that are found can be classified, and normal brains appear
to have somatic variants that were present at birth, variants that accumulate over time, and variants caused by
oxidative damage. Our studies also find a significantly higher rate of sSNV accumulation in neurons from
Alzheimer’s disease (AD) brain, likely related to increased oxidative damage. These studies relied on new
techniques that allow deep whole genome sequencing of DNA isolated from a single neuron taken from frozen
postmortem brain.
 This new study aims to further characterize the rates and patters of somatic variants that accumulate in
single neurons and glia as an individual ages, and determine how this accumulation of mutations is related to
AD as well as the formation of glial tumors. The first aim will examine neurons form different regions of normal
brain at different ages. This will give us a better understanding of how these mutations accumulate with age,
and the specific mutational forces at work in different brain areas. The second aim will perform a similar
analysis, this time focused on glial cells instead of neurons. In the final aim, we will look at neurons in the
brains of individuals who had AD, and analyze how the rate and patter of mutations differ compared to aged-
matched normal brain. This will provide valuable insight into the causes of somatic mutations in AD.
 There is compelling evidence to suggest that somatic mutations in individual neurons are an important
factor in at least some neurodegenerative disorders, and our data implicate them in normal cognitive aging.
For the first time, the tools exist to examine these questions, and this study is designed to determine how
somatic SNV impact normal aging, brain tumor formation, and AD. This is a crucial step in understanding the
molecular cause of AD, and a prerequisite to the development of treatments and cures.

## Key facts

- **NIH application ID:** 10376742
- **Project number:** 5R01AG070921-02
- **Recipient organization:** BOSTON CHILDREN'S HOSPITAL
- **Principal Investigator:** Alice Eunjung Lee
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $865,985
- **Award type:** 5
- **Project period:** 2021-04-01 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10376742

## Citation

> US National Institutes of Health, RePORTER application 10376742, Rates and mechanisms of age-related somatic mutation in normal and Alzheimer brain (5R01AG070921-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10376742. Licensed CC0.

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