Influence of alpha-synuclein on glucose metabolism in Alzheimer's disease continuum: Analyses of α-synuclein seed amplification assay and FDG-PET

IF 13 1区医学 Q1 CLINICAL NEUROLOGY

Alzheimer's & Dementia Pub Date : 2025-02-12 DOI:10.1002/alz.14571

Elijah Mak, Scott A. Przybelski, Heather J. Wiste, Angela J. Fought, Christopher G. Schwarz, Matthew L. Senjem, Clifford R. Jack Jr., Val J. Lowe, Ronald C. Petersen, Bradley F. Boeve, John T. O'Brien, Kejal Kantarci, for the Alzheimer's Disease Neuroimaging Initiative

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引用次数: 0

Abstract

INTRODUCTION

We investigated the association between alpha-synuclein (α-syn) pathology and brain glucose metabolism across the cognitive spectrum of Alzheimer's disease (AD) co-pathologies.

METHODS

Fluorodeoxyglucose positron emission tomography (FDG-PET) data from 829 Alzheimer's Disease Neuroimaging Initiative participants (648 cognitively impaired [CI], 181 unimpaired [CU]) were compared between α-syn seed amplification assay (SAA) positive and negative groups. Interactions with cerebrospinal fluid (CSF) AD biomarkers were examined.

RESULTS

SAA+ was associated with widespread hypometabolism among CI individuals, particularly in posterior cortical regions, independent of CSF amyloid and tau levels in the occipital lobes. Regional hypometabolism mediated the effect of α-syn SAA on disease severity in CI individuals, independent of CSF amyloid and tau levels. There were no influences of SAA on FDG-PET in CU individuals.

DISCUSSION

This study supports a model in which α-syn aggregation influences metabolic dysfunction, which then influences clinical disease severity, independent of AD. SAA+ could help optimize participant selection and outcome measures for clinical trials in AD.

Highlights

α-synuclein seed amplification positivity (SAA+) was associated with hypometabolism in cognitively impaired individuals.
Hypometabolism mediated the influence of α-synuclein on disease severity.
Occipital hypometabolism in SAA+ was independent of cerebrospinal fluid levels of Alzheimer's disease pathology.
These findings can optimize future clinical trials targeting α-synuclein pathology.

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来源期刊

Alzheimer's & Dementia 医学-临床神经学

CiteScore

14.50

自引率

5.00%

发文量

299

审稿时长

3 months

期刊介绍： Alzheimer's & Dementia is a peer-reviewed journal that aims to bridge knowledge gaps in dementia research by covering the entire spectrum, from basic science to clinical trials to social and behavioral investigations. It provides a platform for rapid communication of new findings and ideas, optimal translation of research into practical applications, increasing knowledge across diverse disciplines for early detection, diagnosis, and intervention, and identifying promising new research directions. In July 2008, Alzheimer's & Dementia was accepted for indexing by MEDLINE, recognizing its scientific merit and contribution to Alzheimer's research.