# Locus-coeruleus function in normal elderly and AD risk (LEAD)

> **NIH NIH R21** · NEW YORK UNIVERSITY SCHOOL OF MEDICINE · 2020 · $229,250

## Abstract

PROJECT SUMMARY
 Alzheimer's disease (AD) is a common neurodegenerative disease characterized by the accumulation of
amyloid plaques and neurofibrillary tangles. Current consensus is that the AD pathological process begins
decades before clinical symptoms occur. This long ‘preclinical’ phase of AD can first be observable in middle-
age as deposits of hyperphosphorylated tau (P-tau) in the transentorhinal cortex and subcortical nuclei such as
the locus coeruleus (LC) and the nucleus basalis of Meynert. We have strong preliminary evidence showing that
higher cerebrospinal fluid (CSF) levels of tau in cognitively normal older adults (mean age: 69.6±8.6 years) are
associated with poorer REM sleep and sleep spindles characteristics, the same processes influenced by the LC.
We also have broad evidence of lower NET uptake in the LC associated with stress and aging. Our study model
poses that early onset of tauopathy in the LC results in chronic upregulation of LC activity. This would reflect
on disruption of the two sleep phenomena dependent on LC silences (REM sleep and sleep spindles), also
closely related to cognition and memory formation, as well as performance in task-attention tests. Further, we
hypothesize that the now mostly accepted LC tracer [11C] MRB developed and extensively tested by our team,
will show decreased uptake in the LC associated with CSF tau biomarkers and LC tonic and phasic dysfunction.
We propose to test this hypothesis first by demonstrating that increases in CSF tau are associated in vivo with
lower [11C]MRB PET uptake (Aim 1), and that lower [11C] MRB binding in the LC is associated with impaired
REM sleep and sleep spindles characteristics (Aim 2), as well as lower measures of performance in task-related
attention tests (Aim 3). To test these hypotheses, 30 older adults (age 60-75) balanced by sex, will first perform
a full clinical evaluation and MRI (visits 1-2). Subjects will later undergo 7 days of actigraphy followed by
nocturnal polysomnography (NPSG) (visit 3). A morning lumbar puncture (LP) will be performed after NPSG
to obtain CSF, followed by attention tests. LC function will be analyzed by PET-MR using [11C] MRB, which
will be performed 1-4 weeks after the LP (visit 4). There is the potential to identify: 1) an association between
CSF tau and in vivo [11C] MRB uptake; 2) a mechanism by which tau pathology may contribute to sleep
dysfunction; 3) evidence that LC dysfunction disrupts performance in attention tests; and, 4) LC dysfunction as
a new therapeutic target for AD prevention.

## Key facts

- **NIH application ID:** 9969971
- **Project number:** 1R21AG067549-01
- **Recipient organization:** NEW YORK UNIVERSITY SCHOOL OF MEDICINE
- **Principal Investigator:** YU-SHIN DING
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $229,250
- **Award type:** 1
- **Project period:** 2020-06-01 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9969971

## Citation

> US National Institutes of Health, RePORTER application 9969971, Locus-coeruleus function in normal elderly and AD risk (LEAD) (1R21AG067549-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9969971. Licensed CC0.

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