Associations of Blood Biomarkers of Glial Cell Dysfunction and Neuronal Injury With Future Cognitive Decline and Incident Dementia

Authors

• Srishti Shrestha
• Xiaoqian Zhu
• B Gwen Windham
• Kevin J Sullivan
• Priya Palta
• Rebecca F Gottesman
• Russell P Tracy
• Clifford R Jack
• Petrice M Cogswell
• Prashanthi Vemuri
• Sudha Seshadri
• Thomas H Mosley
• Michael E Griswold
• Myriam Fornage

Language

English

Publication Date

5-1-2026

Journal

Alzheimer's & Dementia

DOI

10.1002/alz.71422

PMID

42092335

PMCID

PMC13149226

PubMedCentral® Posted Date

5-6-2026

PubMedCentral® Full Text Version

Post-print

Abstract

Introduction: Prospective studies of blood-based biomarkers reflecting pathogenic processes, other than Alzheimer-specific pathologies, that contribute to dementia in diverse cohorts are lacking.

Methods: We jointly fitted linear mixed-effect models and proportional hazards models to examine associations of midlife glial fibrillary acidic protein (GFAP), chitinase-3-like protein 1 (YKL-40), soluble cluster of differentiation-14 (sCD14), neurofilament light chain (NfL), total tau (t-tau), and ubiquitin C-terminal hydrolase L1 (UCHL1) levels in serum (collected in 1993 to 1995) with cognitive decline and incident dementia (ascertained over 29 years through 2022) in the community-based Atherosclerosis Risk in Communities Study. sCD14 and YKL-40 were measured in 3082 participants and the other four biomarkers in 1766 participants.

Results: Higher serum GFAP, YKL-40, sCD14, and NfL were associated with faster cognitive decline and elevated dementia rate (e.g., 1 standard deviation [SD] higher log-base2 YKL-40 was associated with -0.11SD faster 25-year cognitive decline (95% confidence interval [CI]: -0.15,-0.07) and 45% higher dementia hazard (hazard ratio [HR]: 1.45 [95% CI: 1.25, 1.68]). Higher t-tau and UCHL1 were also associated with faster cognitive decline.

Discussion: Midlife blood biomarkers reflecting glial and neuronal dysfunction and neuroinflammation are associated with early cognitive impairment.

Keywords

Humans, Biomarkers, Male, Female, Neuroglia, Chitinase-3-Like Protein 1, Cognitive Dysfunction, Dementia, Glial Fibrillary Acidic Protein, Aged, Ubiquitin Thiolesterase, Middle Aged, Neurons, Neurofilament Proteins, tau Proteins, Prospective Studies, Lipopolysaccharide Receptors, Incidence, ARIC study, blood‐based biomarkers, cognitive decline, glial fibrillary acidic protein, GFAP, incident dementia, neurofilament light chain, NfL, soluble cluster of differentiation‐14, sCD14, ubiquitin C‐terminal hydrolase L1, UCHL1, chitinase‐3‐like protein 1, YKL‐40

Published Open-Access

yes

Recommended Citation

Shrestha, Srishti; Zhu, Xiaoqian; Windham, B Gwen; et al., "Associations of Blood Biomarkers of Glial Cell Dysfunction and Neuronal Injury With Future Cognitive Decline and Incident Dementia" (2026). Faculty, Staff and Student Publications. 1431.
https://digitalcommons.library.tmc.edu/uthsph_docs/1431