# Genome-Wide Somatic Mutation in Alzheimer's Disease Pathogenesis Using Single Neuron Analysis

> **NIH NIH K08** · BRIGHAM AND WOMEN'S HOSPITAL · 2020 · $169,560

## Abstract

PROJECT SUMMARY / ABSTRACT
 This NIH K08 proposal describes a five-year career development training program in neurodegenerative
disease genomics research. Dr. Michael Miller has completed clinical residency in Anatomic Pathology and
fellowship in Neuropathology at Brigham and Women’s Hospital (BWH) and Boston Children’s Hospital (BCH)
at Harvard Medical School (HMS), and will embark on this research program to train for an independent
academic research career to investigate the pathogenesis of neurodegenerative disease.
 In this training program, Dr. Miller will develop expertise in single cell genomics, next-generation
sequencing data analysis, biologic interpretation of non-neoplastic human somatic mutations, and application
of genomic approaches toward neurodegenerative disease mechanistic inquiry. His mentor, Dr. Christopher
Walsh (a Professor of Neurology at HMS and HHMI Investigator at BCH), is a leader in human neurologic
disease genetics and genomics. His laboratory has extensive experience in human genetics, neurologic
disease gene mapping, single cell genomics, and analysis of large data sets. Dr. Walsh has established a long
track record for mentoring other trainees to successful careers in biomedical research. In addition, Dr. Miller
has assembled a group of collaborators with complementary expertise, and an Advisory Committee with
extensive experience in mentoring physician-scientists to develop independent research programs. He will
supplement this training with didactic courses and presentation of work at international and national meetings.
 The primary scientific objective of the proposed research plan is to study the role of neuronal somatic
mutation in Alzheimer’s disease (AD). Dr. Miller provides pilot data indicating that neurons in AD show
substantial genome damage in the form of elevated somatic single nucleotide variants (sSNV) compared to
control neurons. The proposal will examine the disease context for this finding, by studying its distribution in
the AD brain and relationship to known key events in AD cellular pathophysiology: oxidative stress and Tau
misfolding. The central hypothesis of this proposal is that aberrant Tau and oxidative damage drive somatic
mutation in AD, constituting a cascade of cellular damage that underlies disease pathogenesis.
 Single cell whole genome sequencing (scWGS) will be employed to address three independent but related
questions about the role of somatic mutation in AD: (1) sSNV burden will be compared in 3 areas of the brain
affected at different stages in AD, to assess sSNV relationship to disease pathologic advancement; (2)
Somatic mutational signatures will be determined for AD, to identify the proximate causes of sSNV, along with
direct testing for a putative candidate in oxidized DNA; and (3) neurons with greater Tau accumulation will be
examined for sSNV to assess the relationship between cellular pathologic burden and somatic mutations.
These studies will examine a novel pathog...

## Key facts

- **NIH application ID:** 9871702
- **Project number:** 1K08AG065502-01
- **Recipient organization:** BRIGHAM AND WOMEN'S HOSPITAL
- **Principal Investigator:** Michael B Miller
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $169,560
- **Award type:** 1
- **Project period:** 2020-03-01 → 2025-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9871702

## Citation

> US National Institutes of Health, RePORTER application 9871702, Genome-Wide Somatic Mutation in Alzheimer's Disease Pathogenesis Using Single Neuron Analysis (1K08AG065502-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9871702. Licensed CC0.

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