Catecholaminergic nucleus integrity and Alzheimer's pathology, symptoms, and progression
Author(s)
Type
Journal Article
Abstract
BACKGROUND
The noradrenergic locus coeruleus (LC) accumulates pathology early in Alzheimer's disease (AD), with LC dysfunction contributing to symptoms and disease progression. We investigated LC and substantia nigra (SN) integrity in healthy controls and AD participants.
METHODS
Ninety-three AD participants and 29 controls underwent neuromelanin magnetic resonance imaging. LC and SN contrast, reflecting nucleus integrity, related to cognitive and neuropsychiatric symptoms, as well as cognitive decline and atrophy rates.
RESULTS
LC – but not SN – integrity was reduced in AD versus controls (b = −0.39, p = 0.001) and within AD was associated with global cognition (b = 8.53, p = 0.04) and neuropsychiatric symptoms, accounting for SN. An AD subgroup with reduced SN integrity had worse cognition. LC integrity predicted plasma phosphorylated tau protein 217 (b = −0.30, p = 0.03). Lower LC and SN integrities were both related to faster cognitive decline (LC: b = −4.74, p = 0.048; SN: b = −2.27, p = 0.03), accounting for one another.
DISCUSSION
Catecholaminergic nucleus integrity plays an important role in AD. Both systems are relevant to cognitive performance and decline. LC, in particular, relates closely to symptoms, pathology, and rate of progression.
Highlights
In symptomatic AD, LC integrity reflects cortical AD pathology, measured by pTau217.
LC integrity predicts cognitive function in AD, independent of cortical atrophy.
LC and SN integrity independently relate to attentional performance.
Symptoms of anxiety, depression, and apathy are associated with lower LC integrity.
LC and SN relate to cognitive decline rate and left LC predicts atrophy rate.
The noradrenergic locus coeruleus (LC) accumulates pathology early in Alzheimer's disease (AD), with LC dysfunction contributing to symptoms and disease progression. We investigated LC and substantia nigra (SN) integrity in healthy controls and AD participants.
METHODS
Ninety-three AD participants and 29 controls underwent neuromelanin magnetic resonance imaging. LC and SN contrast, reflecting nucleus integrity, related to cognitive and neuropsychiatric symptoms, as well as cognitive decline and atrophy rates.
RESULTS
LC – but not SN – integrity was reduced in AD versus controls (b = −0.39, p = 0.001) and within AD was associated with global cognition (b = 8.53, p = 0.04) and neuropsychiatric symptoms, accounting for SN. An AD subgroup with reduced SN integrity had worse cognition. LC integrity predicted plasma phosphorylated tau protein 217 (b = −0.30, p = 0.03). Lower LC and SN integrities were both related to faster cognitive decline (LC: b = −4.74, p = 0.048; SN: b = −2.27, p = 0.03), accounting for one another.
DISCUSSION
Catecholaminergic nucleus integrity plays an important role in AD. Both systems are relevant to cognitive performance and decline. LC, in particular, relates closely to symptoms, pathology, and rate of progression.
Highlights
In symptomatic AD, LC integrity reflects cortical AD pathology, measured by pTau217.
LC integrity predicts cognitive function in AD, independent of cortical atrophy.
LC and SN integrity independently relate to attentional performance.
Symptoms of anxiety, depression, and apathy are associated with lower LC integrity.
LC and SN relate to cognitive decline rate and left LC predicts atrophy rate.
Date Issued
2025-10-01
Date Acceptance
2025-09-02
Citation
Alzheimer's and Dementia, 2025, 21 (10)
ISSN
1552-5260
Publisher
Wiley
Journal / Book Title
Alzheimer's and Dementia
Volume
21
Issue
10
Copyright Statement
© 2025 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
License URL
Identifier
https://www.ncbi.nlm.nih.gov/pubmed/41023472
Subjects
catecholamines
cognition
disease progression
dopamine
locus coeruleus
neuromelanin
neuropsychiatric symptoms
noradrenaline
norepinephrine
substantia nigra
Humans
Alzheimer Disease
Female
Male
Disease Progression
Locus Coeruleus
Aged
Magnetic Resonance Imaging
Substantia Nigra
Cognitive Dysfunction
Neuropsychological Tests
Atrophy
Melanins
tau Proteins
Aged, 80 and over
Publication Status
Published
Coverage Spatial
United States
Article Number
e70749
Date Publish Online
2025-09-29