# Leukocyte Telomere Length, Mitochondrial DNA Copy Number, Plasma Proteomics, and Alzheimer's Disease-related Dementia

> **NIH NIH R21** · UNIVERSITY OF MINNESOTA · 2021 · $132,704

## Abstract

Project Summary
Alzheimer’s disease and related dementias (ADRD) affect 47 million individuals world-wide. The etiology of
ADRD is complex and not well understood, and there are few treatment options. ADRD has a long preclinical
stage ranging from years to decades. There is thus potential for early preventive and treatment interventions
by targeting risk factors and biological mechanisms in midlife. Shortened leukocyte telomere length (LTL) and
reduced mitochondrial DNA copy number (MTCN), important aging biomarkers, have recently been implicated
in the pathogenesis of ADRD. However, the underlying mechanisms mediating their associations with ADRD
are not understood. It is important to establish whether LTL and peripheral MTCN measured in midlife predict
the risk of ADRD in prospective studies, and to evaluate the downstream pathways by which shortened LTL
and reduced MTCN may lead to the development of ADRD. Finding from such work could provide etiologic
insights that may inform targeted pathways for prevention and early intervention. This R21 study will utilize
existing data from the Atherosclerosis Risk in Communities Neurocognitive Study (ARIC-NCS), the NHLBI
Trans-Omics for Precision Medicine (TOPMed), and NHGRI Centers for Common Disease Genomics (CCDG)
programs. ARIC-NCS (baseline n: 15,792; age: 45-64y) has identified 2,719 incident dementia cases over 30
years of follow-up. We have obtained estimates for LTL and leukocyte MTCN (l-MTCN) for 3,353 ARIC
participants based on visits 2 or 3 whole genome sequencing (WGS) data from TOPMed. Our preliminary
analysis of this sample suggests that 1) midlife LTL and l-MTCN are associated with future risk of dementia
and 2) an unbiased proteomics analysis (i.e. 4,931 proteins from the aptamer-based SOMAscan v.4 plasma
proteomics panel) can identify functionally relevant proteins for LTL and l-MTCN. Our objectives are to: (1)
Complete the estimates for LTL and l-MTCN for the remaining ARIC participants (n=10,193) using ARIC WGS
data available through CCDG. (2) Assess the prospective association of LTL and l-MTCN measured in middle
age with dementia incidence in whole ARIC cohort. (3) Leverage the SOMAScan proteomics data, available for
the entire ARIC cohort from visits 2 and 3, to conduct a proteomics analysis of LTL and l-MTCN. We will also
conduct a proteomics analysis of genetic polygenic risk scores (PRS) for LTL, that we will derive using a
published LTL GWAS and categorize into different gene-based pathways. (4) Conduct a mediation analysis to
evaluate which of the proteins identified in (3) above may mediate the associations of LTL and l-MTCN with
incident dementia.
This study will use ARIC’s multi-omics resources to evaluate the associations of midlife LTL and l-MTCN with
ADRD, and to identify proteomics signatures of these aging biomarkers that are relevant to the etiology of
ADRD, with the broad objective of improving the prevention and treatment of ADRD.

## Key facts

- **NIH application ID:** 10420508
- **Project number:** 3R21AG072530-01S1
- **Recipient organization:** UNIVERSITY OF MINNESOTA
- **Principal Investigator:** Weihong Tang
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $132,704
- **Award type:** 3
- **Project period:** 2021-06-01 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10420508

## Citation

> US National Institutes of Health, RePORTER application 10420508, Leukocyte Telomere Length, Mitochondrial DNA Copy Number, Plasma Proteomics, and Alzheimer's Disease-related Dementia (3R21AG072530-01S1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10420508. Licensed CC0.

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