Association of Plasma YKL-40 With MRI, CSF, and Cognitive Markers of Brain Health and Dementia

Matthew P. Pase, Jayandra J. Himali, Raquel Puerta, Alexa S. Beiser, Mitzi M. Gonzales, Claudia L. Satizabal, Qiong Yang, Hugo J. Aparicio, Daniel J. Kojis, Charles S. Decarli, Oscar L. Lopez, Will Longstreth, Vilmundur Gudnason, Thomas H. Mosley, Joshua C. Bis, Alison Fohner, Bruce M. Psaty, Mercè Boada, Pablo García-González, Sergi ValeroMarta Marquié, Russell Tracy, Lenore J. Launer, Agustín Ruiz, Myriam Fornage, Sudha Seshadri

Research output: Contribution to journalArticlepeer-review


BACKGROUND AND OBJECTIVES: Higher YKL-40 levels in the CSF are a known biomarker of brain inflammation. We explored the utility of plasma YKL-40 as a biomarker for accelerated brain aging and dementia risk. METHODS: We performed cross-sectional and prospective analyses of 4 community-based cohorts in the United States or Europe: the Age, Gene/Environment Susceptibility-Reykjavik Study, Atherosclerosis Risk in the Communities study, Coronary Artery Risk Development in Young Adults study, and Framingham Heart Study (FHS). YKL-40 was measured from stored plasma by a single laboratory using Mesoscale Discovery with levels log transformed and standardized within each cohort. Outcomes included MRI total brain volume, hippocampal volume, and white matter hyperintensity volume (WMHV) as a percentage of intracranial volume, a general cognitive composite derived from neuropsychological testing (SD units [SDU]), and the risk of incident dementia. We sought to replicate associations with dementia in the clinic-based ACE csf cohort, which also had YKL-40 measured from the CSF. RESULTS: Meta-analyses of MRI outcomes included 6,558 dementia-free participants, and for analysis of cognition, 6,670. The blood draw preceded MRI/cognitive assessment by up to 10.6 years across cohorts. The mean ages ranged from 50 to 76 years, with 39%-48% male individuals. In random-effects meta-analysis of study estimates, each SDU increase in log-transformed YKL-40 levels was associated with smaller total brain volume (β = -0.33; 95% CI -0.45 to -0.22; p < 0.0001) and poorer cognition (β = -0.04; 95% CI -0.07 to -0.02; p < 0.01), following adjustments for demographic variables. YKL-40 levels did not associate with hippocampal volume or WMHV. In the FHS, each SDU increase in log YKL-40 levels was associated with a 64% increase in incident dementia risk over a median of 5.8 years of follow-up, following adjustments for demographic variables (hazard ratio 1.64; 95% CI 1.25-2.16; p < 0.001). In the ACE csf cohort, plasma and CSF YKL-40 were correlated (r = 0.31), and both were associated with conversion from mild cognitive impairment to dementia, independent of amyloid, tau, and neurodegeneration status. DISCUSSION: Higher plasma YKL-40 levels were associated with lower brain volume, poorer cognition, and incident dementia. Plasma YKL-40 may be useful for studying the association of inflammation and its treatment on dementia risk.

Original languageEnglish (US)
Pages (from-to)e208075
Issue number4
StatePublished - Feb 27 2024
Externally publishedYes

ASJC Scopus subject areas

  • Clinical Neurology


Dive into the research topics of 'Association of Plasma YKL-40 With MRI, CSF, and Cognitive Markers of Brain Health and Dementia'. Together they form a unique fingerprint.

Cite this