Elevated locus coeruleus metabolism provides resilience against cognitive decline in preclinical Alzheimer's disease

Elouise A. Koops; Joyita Dutta; Bernard J. Hanseeuw; J. Alex Becker; Maxime Van Egroo; Prokopis C. Prokopiou; Julie C. Price; Steven E. Arnold; Reisa A. Sperling; Keith A. Johnson; Heidi I. L. Jacobs

doi:10.1002/alz.14385

Elevated locus coeruleus metabolism provides resilience against cognitive decline in preclinical Alzheimer's disease

Elouise A. Koops, Joyita Dutta, Bernard J. Hanseeuw, J. Alex Becker, Maxime Van Egroo, Prokopis C. Prokopiou, Julie C. Price, Steven E. Arnold, Reisa A. Sperling, Keith A. Johnson, Heidi I. L. Jacobs^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

Abstract

INTRODUCTION: Alterations in locus coeruleus’ (LC) metabolic turnover are associated with Alzheimer's disease (AD)-pathology and cognitive impairment. However, the evolution of these changes across disease stages and their functional relevance remains unknown. METHODS: We examined associations of [ ¹⁸F]-fluorodeoxyglucose positron emission tomography (FDG-PET) -derived LC metabolism with clinical diagnostic status, cerebrospinal fluid (CSF) -based AD biomarkers of AD pathology, and cognitive decline in Alzheimer's Disease Neuroimaging Initiative (ADNI) participants (n = 604). RESULTS: FDG-PET-derived LC metabolism was elevated in the earliest preclinical stages and lower in later disease stages. Higher LC metabolism was associated with attenuated memory decline in preclinical stages, particularly in those with low CSF Aβ _42, but not in AD patients with cognitive impairment. DISCUSSION: Higher locus coeruleus [ ¹⁸F]-FDG-PET-derived signal in the early preclinical stages of AD can confer cognitive resilience and may reflect increased metabolic activity, whereas later stages are characterized by lower LC FDG-PET-derived signal, possibly due to neurodegeneration. Highlights: LC FDG-PET signal is lower in Alzheimer's disease (AD) patients. LC FDG-PET signal is higher in the preclinical stage of AD. We observed less memory decline in those with higher LC FDG-PET signal. Higher LC FDG-PET signal conferred cognitive resilience in preclinical AD.

Original language	English
Article number	e14385
Number of pages	14
Journal	Alzheimer's & Dementia
Volume	21
Issue number	1
Early online date	1 Nov 2024
DOIs	https://doi.org/10.1002/alz.14385
Publication status	Published - Jan 2025

Keywords

Alzheimer's Disease
biomarkers
cognitive decline
CSF
disease staging
FDG-PET
locus coeruleus
MRI
neuromodulatory subcortical systems
PET
preclinical
VASOACTIVE-INTESTINAL-PEPTIDE
AMYLOID-BETA
DEMENTIA
TAU
NOREPINEPHRINE
OLIGOMERS
MHPG
NORADRENALINE
SEGMENTATION
DEFINITION

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Koops, E. A., Dutta, J., Hanseeuw, B. J., Becker, J. A., Van Egroo, M., Prokopiou, P. C., Price, J. C., Arnold, S. E., Sperling, R. A., Johnson, K. A., & Jacobs, H. I. L. (2025). Elevated locus coeruleus metabolism provides resilience against cognitive decline in preclinical Alzheimer's disease. Alzheimer's & Dementia, 21(1), Article e14385. https://doi.org/10.1002/alz.14385

@article{e3d06ffedd4b47aab7a32a3d77d1e5d9,

title = "Elevated locus coeruleus metabolism provides resilience against cognitive decline in preclinical Alzheimer's disease",

abstract = "INTRODUCTION: Alterations in locus coeruleus{\textquoteright} (LC) metabolic turnover are associated with Alzheimer's disease (AD)-pathology and cognitive impairment. However, the evolution of these changes across disease stages and their functional relevance remains unknown. METHODS: We examined associations of [ 18F]-fluorodeoxyglucose positron emission tomography (FDG-PET) -derived LC metabolism with clinical diagnostic status, cerebrospinal fluid (CSF) -based AD biomarkers of AD pathology, and cognitive decline in Alzheimer's Disease Neuroimaging Initiative (ADNI) participants (n = 604). RESULTS: FDG-PET-derived LC metabolism was elevated in the earliest preclinical stages and lower in later disease stages. Higher LC metabolism was associated with attenuated memory decline in preclinical stages, particularly in those with low CSF Aβ 42, but not in AD patients with cognitive impairment. DISCUSSION: Higher locus coeruleus [ 18F]-FDG-PET-derived signal in the early preclinical stages of AD can confer cognitive resilience and may reflect increased metabolic activity, whereas later stages are characterized by lower LC FDG-PET-derived signal, possibly due to neurodegeneration. Highlights: LC FDG-PET signal is lower in Alzheimer's disease (AD) patients. LC FDG-PET signal is higher in the preclinical stage of AD. We observed less memory decline in those with higher LC FDG-PET signal. Higher LC FDG-PET signal conferred cognitive resilience in preclinical AD.",

keywords = "Alzheimer's Disease, biomarkers, cognitive decline, CSF, disease staging, FDG-PET, locus coeruleus, MRI, neuromodulatory subcortical systems, PET, preclinical, VASOACTIVE-INTESTINAL-PEPTIDE, AMYLOID-BETA, DEMENTIA, TAU, NOREPINEPHRINE, OLIGOMERS, MHPG, NORADRENALINE, SEGMENTATION, DEFINITION",

author = "Koops, {Elouise A.} and Joyita Dutta and Hanseeuw, {Bernard J.} and Becker, {J. Alex} and {Van Egroo}, Maxime and Prokopiou, {Prokopis C.} and Price, {Julie C.} and Arnold, {Steven E.} and Sperling, {Reisa A.} and Johnson, {Keith A.} and Jacobs, {Heidi I. L.}",

year = "2025",

month = jan,

doi = "10.1002/alz.14385",

language = "English",

volume = "21",

journal = "Alzheimer's & Dementia",

issn = "1552-5260",

publisher = "John Wiley & Sons Inc.",

number = "1",

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TY - JOUR

T1 - Elevated locus coeruleus metabolism provides resilience against cognitive decline in preclinical Alzheimer's disease

AU - Koops, Elouise A.

AU - Dutta, Joyita

AU - Hanseeuw, Bernard J.

AU - Becker, J. Alex

AU - Van Egroo, Maxime

AU - Prokopiou, Prokopis C.

AU - Price, Julie C.

AU - Arnold, Steven E.

AU - Sperling, Reisa A.

AU - Johnson, Keith A.

AU - Jacobs, Heidi I. L.

PY - 2025/1

Y1 - 2025/1

N2 - INTRODUCTION: Alterations in locus coeruleus’ (LC) metabolic turnover are associated with Alzheimer's disease (AD)-pathology and cognitive impairment. However, the evolution of these changes across disease stages and their functional relevance remains unknown. METHODS: We examined associations of [ 18F]-fluorodeoxyglucose positron emission tomography (FDG-PET) -derived LC metabolism with clinical diagnostic status, cerebrospinal fluid (CSF) -based AD biomarkers of AD pathology, and cognitive decline in Alzheimer's Disease Neuroimaging Initiative (ADNI) participants (n = 604). RESULTS: FDG-PET-derived LC metabolism was elevated in the earliest preclinical stages and lower in later disease stages. Higher LC metabolism was associated with attenuated memory decline in preclinical stages, particularly in those with low CSF Aβ 42, but not in AD patients with cognitive impairment. DISCUSSION: Higher locus coeruleus [ 18F]-FDG-PET-derived signal in the early preclinical stages of AD can confer cognitive resilience and may reflect increased metabolic activity, whereas later stages are characterized by lower LC FDG-PET-derived signal, possibly due to neurodegeneration. Highlights: LC FDG-PET signal is lower in Alzheimer's disease (AD) patients. LC FDG-PET signal is higher in the preclinical stage of AD. We observed less memory decline in those with higher LC FDG-PET signal. Higher LC FDG-PET signal conferred cognitive resilience in preclinical AD.

AB - INTRODUCTION: Alterations in locus coeruleus’ (LC) metabolic turnover are associated with Alzheimer's disease (AD)-pathology and cognitive impairment. However, the evolution of these changes across disease stages and their functional relevance remains unknown. METHODS: We examined associations of [ 18F]-fluorodeoxyglucose positron emission tomography (FDG-PET) -derived LC metabolism with clinical diagnostic status, cerebrospinal fluid (CSF) -based AD biomarkers of AD pathology, and cognitive decline in Alzheimer's Disease Neuroimaging Initiative (ADNI) participants (n = 604). RESULTS: FDG-PET-derived LC metabolism was elevated in the earliest preclinical stages and lower in later disease stages. Higher LC metabolism was associated with attenuated memory decline in preclinical stages, particularly in those with low CSF Aβ 42, but not in AD patients with cognitive impairment. DISCUSSION: Higher locus coeruleus [ 18F]-FDG-PET-derived signal in the early preclinical stages of AD can confer cognitive resilience and may reflect increased metabolic activity, whereas later stages are characterized by lower LC FDG-PET-derived signal, possibly due to neurodegeneration. Highlights: LC FDG-PET signal is lower in Alzheimer's disease (AD) patients. LC FDG-PET signal is higher in the preclinical stage of AD. We observed less memory decline in those with higher LC FDG-PET signal. Higher LC FDG-PET signal conferred cognitive resilience in preclinical AD.

KW - Alzheimer's Disease

KW - biomarkers

KW - cognitive decline

KW - CSF

KW - disease staging

KW - FDG-PET

KW - locus coeruleus

KW - MRI

KW - neuromodulatory subcortical systems

KW - PET

KW - preclinical

KW - VASOACTIVE-INTESTINAL-PEPTIDE

KW - AMYLOID-BETA

KW - DEMENTIA

KW - TAU

KW - NOREPINEPHRINE

KW - OLIGOMERS

KW - MHPG

KW - NORADRENALINE

KW - SEGMENTATION

KW - DEFINITION

U2 - 10.1002/alz.14385

DO - 10.1002/alz.14385

M3 - Article

SN - 1552-5260

VL - 21

JO - Alzheimer's & Dementia

JF - Alzheimer's & Dementia

IS - 1

M1 - e14385

ER -

Elevated locus coeruleus metabolism provides resilience against cognitive decline in preclinical Alzheimer's disease

Abstract

Keywords

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