# Mechanistic Basis of the mtDNA Haplogroup J-Alzheimer's Disease Association

> **NIH NIH R01** · UNIVERSITY OF KANSAS MEDICAL CENTER · 2020 · $382,500

## Abstract

PROJECT SUMMARY
 Extensive research ties mitochondria to Alzheimer's disease (AD), but how mitochondria contribute to AD
risk or progression remains unsettled. Here, we build on new and compelling data that indicate the
mitochondrial DNA (mtDNA) haplogroup J occurs in higher frequencies in persons with AD. This finding argues
mitochondria independently contribute to AD, and is particularly unexpected as increased haplogroup J
frequency paradoxically also occurs in the oldest old. Four specific haplogroup J-defining polymorphisms
appear to drive the association; three reside in the mtDNA control region that regulates mtDNA replication and
transcription, and the fourth is a non-synonymous ND5 variant. These variants travel together and currently we
cannot tell whether the control region variants, the protein-coding variant, or a combination contributes to AD
risk. To resolve this and gain new AD mechanistic insight, we propose a synergistic two-aim, bench-and-
bedside approach that will extend these genetic associations to functional associations. In Aim 1, we use
cytoplasmic hybrid (cybrid) cell lines to define how the haplogroup J variants affect mitochondrial function and
integrity. In Aim 2, we use clinical biospecimen and biomarker data to further explore the haplogroup J, AD,
and aging nexus. Thus, in addition to advancing our understanding of AD, our mechanistic analysis of
haplogroup J effects will also inform how mitochondrial biology relates to aging. These studies will provide
insight into mechanisms that cause AD and aging to converge, but also occasionally diverge.

## Key facts

- **NIH application ID:** 9856947
- **Project number:** 5R01AG061194-02
- **Recipient organization:** UNIVERSITY OF KANSAS MEDICAL CENTER
- **Principal Investigator:** RUSSELL H. SWERDLOW
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $382,500
- **Award type:** 5
- **Project period:** 2019-02-01 → 2023-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9856947

## Citation

> US National Institutes of Health, RePORTER application 9856947, Mechanistic Basis of the mtDNA Haplogroup J-Alzheimer's Disease Association (5R01AG061194-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9856947. Licensed CC0.

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