# A noradrenergic mechanism of apathy and motivation deficit in MCI and AD

> **NIH NIH R21** · YALE UNIVERSITY · 2020 · $404,250

## Abstract

SUMMARY/ABSTRACT
As one of the most common symptoms, apathy frequently manifests before cognitive impairment in the
spectrum of Alzheimer’s disease (AD). Persistent apathy plays an important role in rapid functional decline and
significantly impacts the quality of life of individuals with AD. Yet, the neurobiological mechanisms underlying
apathy remain unclear.
 Apathy reflects a general diminution of interest or motivation, a lack of effort in goal-directed behavior.
A growing body of evidence implicates the monoaminergic circuits in motivation and effort. A recent review
suggests that dopamine primarily codes for future reward and promotes reward-directed action but is less
sensitive to anticipated effort. On the other hand, effort is tightly linked to heightened arousal and, with
extensive projections to the thalamus and prefrontal cortex, the locus coeruleus (LC) likely plays a critical role
in sustaining motivated and effortful behavior.
 This exploratory study aims to examine this hypothesis and distinguish the roles of the noradrenergic
(NA) and dopaminergic (DA) circuits in motivated behavior and how NA and DA dysfunction may underlie
apathy in individuals with mild cognitive impairment (MCI) and early stage AD, as compared to healthy
controls. Specifically, the LC is a very small structure and difficult to localize with conventional structural
imaging. Building on previous studies, we have taken advantage of the high neuromelanin content in the LC
and ventral tegmental area/substantia nigra, pars compacta (VTA/SNc) and successfully developed a
probabilistic map of the LC and VTA/SNc in individuals’ native space. By engaging participants in fMRI of a
reward task we will query how the NA and DA circuits respond to timed, effortful behavior to acquire reward
and to behavioral outcomes. We hypothesize that individuals with MCI and early stage AD will demonstrate
reduction in neuromelanin signal contrast in the LC and diminished LC circuit activities and connectivities to
support motivated behavior in link with the clinical severity of apathy.
 We propose to test this hypothesis in 30 patients with MCI and early stage AD and 30 age and sex
matched healthy control participants (HC), with two specific aims: 1) examine whether LC and/or VTA/SNc
neuromelanin signal intensity is diminished in participants with MCI and AD as compared to HC and whether
the reduction in neuromelanin contrast is associated with apathy; 2) examine with fMRI whether LC and/or
VTA/SNc response to reward anticipation and outcome as well as LC/VTA-SNc prefrontal cortical connectivity
are reduced in participants with MCI and AD as compared to HC; and whether these changes are associated
with apathy. We hope that the study will substantiate the role of noradrenergic circuits in an etiology of apathy
in AD. If successful, the study may also have important implications for research of many other clinical
conditions that implicate motivation dysfunction.

## Key facts

- **NIH application ID:** 9895059
- **Project number:** 1R21AG067024-01
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** Chiang-Shan Ray Li
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $404,250
- **Award type:** 1
- **Project period:** 2020-01-15 → 2022-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9895059

## Citation

> US National Institutes of Health, RePORTER application 9895059, A noradrenergic mechanism of apathy and motivation deficit in MCI and AD (1R21AG067024-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9895059. Licensed CC0.

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