# Noradrenergic mechanisms of alcohol's impact on the development of MCI and early stage AD

> **NIH NIH R01** · YALE UNIVERSITY · 2022 · $367,500

## Abstract

ABSTRACT/SUMMARY
Alcohol misuse exacerbates cognitive aging. Prospective studies associate problem drinking to increased risk
and earlier onset of Alzheimer’s disease (AD) and related dementia (ADRD). On the other hand, studies of
mainly social drinkers reported no or mitigating effects of alcohol use on cognitive functions. Thus, alcohol use
may influence the risks of ADRD and the impacts likely depend on the severity of alcohol consumption.
 Whereas the progression of ADRD is typically described in six stages in correlation with accumulation
of neurofibrillary tangles and neuropil threads in the cortex and hippocampus, other studies have implicated
functional and structural changes, including neuronal loss, in the locus coeruleus (LC) in early stage AD. LC
degeneration occurs during healthy aging, and longitudinal studies have suggested the LC as a critical
structure of cognitive reserve, in support of LC noradrenergic (NA) circuit dysfunction in the development of
ADRD. Alcohol misuse may cause allostatic changes in NA signaling and accelerate LC circuit dysfunction
during aging. A substantial body of studies provide evidence for the impact of alcohol misuse on central NA
circuits and NA dysfunction as a critical mechanism linking alcohol misuse and ADRD.
 In support of this mechanistic link, we showed that LC neuromelanin imaging signals decreased more
rapidly with age in heavy as compared to light drinkers. Further, the prefrontal cortex and other structures of
the default mode network, which receives heavy NA projections from the LC, also showed significantly steeper
age-related changes in responses to cognitive control and during resting state in heavy vs. light drinkers.
Building on these data and a literature supporting hippocampal function in emotion memory, we propose to
combine MRI and longitudinal assessments of 120 old adult heavy and non/light drinkers (n=60 each, half
women, age matched) to address three aims: 1) Examine whether age-related changes in LC neuromelanin
signals vary with alcohol use and cognitive impairment and whether LC signals mediate the inter-relationship
between alcohol use and cognitive status; 2) Examine whether and how LC circuit connectivities in response to
cognitive control and emotional memory vary with alcohol use and whether the connectivity strength correlates
with LC neuromelanin signals; and 3) Examine whether and how LC neuromelanin signals and LC circuit
connectivities predict the decline in cognitive function and the potential transition from healthy aging to MCI or
from MCI to early stage AD. We will also perform exploratory analyses to examine sex differences and the
influences of other modifiable risk factors for dementia on the development of MCI and AD.
 The overarching goal of the study is to investigate the effects of alcohol misuse and NA dysfunction on
the development of ADRD. We believe that the findings would not only address a critical mechanism of ADRD
but also shed light on the etio...

## Key facts

- **NIH application ID:** 10401937
- **Project number:** 5R01AG072893-03
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** Chiang-Shan Ray Li
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $367,500
- **Award type:** 5
- **Project period:** 2020-09-30 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10401937

## Citation

> US National Institutes of Health, RePORTER application 10401937, Noradrenergic mechanisms of alcohol's impact on the development of MCI and early stage AD (5R01AG072893-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10401937. Licensed CC0.

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