# Circadian Rest-Activity Rhythms, Metabolomic Profiles, and Incidence of Alzheimer's Disease and Related Dementia in Older Men and Women

> **NIH NIH R01** · UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON · 2021 · $724,817

## Abstract

Alzheimer’s disease and related dementias (ADRD) are highly debilitating disorders and the prevalence is
expected to rise rapidly as the population ages. The causes of ADRD remain poorly understood, and there is a
critical need to identify novel modifiable risk factors as well as biological mechanisms of ADRD. Recent
epidemiological studies, including those published by investigators of the proposed study, suggest that age-
related impairment of the internal circadian clock may play a role in the development of ADRD in older men
and women. However it remains unclear what biological mechanisms may drive the associations between
weakened circadian rhythms and ADRD. Recent applications of metabolomics in epidemiological and clinical
studies suggest that there may be common metabolic pathways associated with both circadian disruption and
ADRD. This raises the possibility that age-related impairment in circadian rhythms may drive metabolic
changes, which in turn lead to the development of ADRD. This hypothesis is further supported by our exciting
metabolomics data from 50 men in the Osteoporotic Fractures in Men (MrOS) study: We found that both
weakened rest-activity rhythms and impaired cognitive function are associated with increases in γ-glutamyl
dipeptides, bile acids, fatty acids and acylcarnitines, but decreases in polyunsaturated fatty acids. Based on
the compelling data from epidemiological studies, as well as the intriguing findings from our metabolomics pilot,
we propose to comprehensively examine characteristics of the rest-activity rhythms and metabolomic profiles
in relation to long-term cognitive outcomes. Our metabolomics study will include 1500 older men and women
with 500 incident dementia cases from two unique and complimentary cohorts, the Women’s Health Initiative
and the MrOS. The current study includes three specific aims and one exploratory aim: Aim 1: Determine the
gender-specific relationships between rest-activity rhythms and long-term cognitive outcomes including ADRD
in older men and women. Aim 2: Identify metabolomics signatures that are associated with characteristics of
rest-activity rhythms and incident ADRD, respectively. Aim 3: Test whether common metabolites and pathways
mediate relationships between rest-activity rhythms and incident ADRD. For the Exploratory Aim, we will
examine the relationship between baseline rest-activity rhythms, changes in metabolomics markers, and long-
term cognitive outcomes in the subset of 300 MrOS participants with repeated serum samples. Our study is
innovative because it focuses on weakened circadian rhythms as a novel risk factor for ADRD. Moreover, it
goes beyond characterizing associations and focuses on identifying metabolic pathways linking rest-activity
rhythms with ADRD in a large population of free-living older adults. The proposed study is significant because
it has the potential to identify predictive and mechanistic biomarkers that may lead to better prevention,
diagnosis a...

## Key facts

- **NIH application ID:** 10144362
- **Project number:** 5R01AG063946-02
- **Recipient organization:** UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
- **Principal Investigator:** Qian Xiao
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $724,817
- **Award type:** 5
- **Project period:** 2020-04-15 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10144362

## Citation

> US National Institutes of Health, RePORTER application 10144362, Circadian Rest-Activity Rhythms, Metabolomic Profiles, and Incidence of Alzheimer's Disease and Related Dementia in Older Men and Women (5R01AG063946-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10144362. Licensed CC0.

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