White matter hyperintensity severity modifies gut metabolite association with cognitive outcomes

Naruchorn Kijpaisalratana, Center for Genomic Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA; Division of Neurology, Department of Medicine, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand; Division of Academic Affairs, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand; Department of Neurology, Massachusetts General Hospital, Boston, MA, USA.
Chia-Ling Phuah, Departments of Neurology and Neurosurgery, Barrow Neurological Institute, Phoenix, AZ, USA; Barrow Neuro Analytics Center, Barrow Neurological Institute, Phoenix, AZ, USA.
Zsuzsanna Ament, Center for Genomic Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA; Department of Neurology, Massachusetts General Hospital, Boston, MA, USA.
Varun M. Bhave, Harvard Medical School, Boston, MA, USA.
Ana-Lucia Garcia-Guarniz, Department of Neurology, Massachusetts General Hospital, Boston, MA, USA.
Jonathan Duskin, Department of Neurology, Massachusetts General Hospital, Boston, MA, USA.
Catharine A. Couch, Department of Epidemiology, School of Public Health, University of Alabama at Birmingham, Birmingham, AL, USA.
M Ryan Irvin, Department of Epidemiology, School of Public Health, University of Alabama at Birmingham, Birmingham, AL, USA.
W Taylor Kimberly, Center for Genomic Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA; Department of Neurology, Massachusetts General Hospital, Boston, MA, USA; Harvard Medical School, Boston, MA, USA. Electronic address: wtkimberly@mgh.harvard.edu.

Document Type

Article

Abstract

BACKGROUND: Gut microbiome-associated metabolites and white matter hyperintensities (WMH) are independently associated with cognitive impairment. However, it is unclear if gut metabolites and WMH interact to influence dementia. OBJECTIVES: To examine the association between gut microbial metabolites and cognitive outcomes and assess whether the severity of baseline WMH would impact associations between gut microbial metabolites and cognitive outcomes. DESIGN: Cross-sectional design. SETTING: Cohort of individuals who are clinically normal, mild cognitive impairment, or Alzheimer's Disease in the Alzheimer's Disease Neuroimaging Initiative (ADNI). PARTICIPANTS: A total of 578 participants with available baseline 3.0T 2D-Fluid Attenuation Inversion Recovery (FLAIR) Magnetic Resonance Imaging (MRI) scans and baseline gut microbial metabolite measurement were included in the analysis. MEASUREMENTS: Gut metabolite measurements and automated WMH volume estimations were obtained from FLAIR MRI and were used to assess the association and interaction with cognitive impairment. RESULTS: Of 104 metabolites studied, glycodeoxycholic acid (GDCA) surpassed the false discovery rate and was associated the Alzheimer's Disease Assessment Scale-Cognitive Subscale version 13 (ADAS-Cog13) score (β = 0.12, 95 % CI = 0.05-0.20, p = 0.001) and cognitive impairment determined by mini-mental status exam (MMSE) (OR = 2.11, 95 % CI = 1.41-3.15, p < 0.001). GDCA was associated with higher ADAS-Cog13 in participants with low WMH burden (β = 0.21, 95% CI = 0.10-0.32, p < 0.001) but not in participants with high WMH burden (β = 0.04, 95 % CI = -0.07 to 0.14, p = 0.48; interaction p = 0.02). CONCLUSION: An elevated level of GDCA was associated with worse cognition. WMH severity modified the association between GDCA and cognitive outcomes.

Medical Subject Headings

Humans; White Matter (diagnostic imaging, pathology); Male; Female; Cross-Sectional Studies; Magnetic Resonance Imaging; Gastrointestinal Microbiome (physiology); Cognitive Dysfunction (metabolism, diagnostic imaging); Aged; Alzheimer Disease (metabolism, diagnostic imaging); Cognition (physiology); Severity of Illness Index

Publication Date

4-1-2025

Publication Title

The journal of prevention of Alzheimer's disease

E-ISSN

2426-0266

Volume

12

Issue

4

First Page

100086

PubMed ID

39939193

Digital Object Identifier (DOI)

10.1016/j.tjpad.2025.100086

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