CSF YKL-40 and pTau181 are related to different cerebral morphometric patterns in early AD

Cerebrospinal fluid (CSF) concentrations of YKL-40 that serve as biomarker of neuroinflammation are known to be altered along the clinico-biological continuum of Alzheimer's disease (AD). The specific structural cerebral correlates of CSF YKL-40 were evaluated across the early stages of AD from normal to preclinical to mild dementia. Nonlinear gray matter (GM) volume associations with CSF YKL-40 levels were assessed in a total of 116 subjects, including normal controls and those with preclinical AD as defined by CSF Aβ < 500 pg/mL, mild cognitive impairment (MCI) due to AD, or mild AD dementia. Age-corrected YKL-40 levels were increased in MCIs versus the rest of groups and showed an inverse u-shaped association with p-tau values. A similar nonlinear relationship was found between GM volume and YKL-40 in inferior and lateral temporal regions spreading to the supramarginal gyrus, insula, inferior frontal cortex, and cerebellum in MCI and AD. These findings for YKL-40 remained unchanged after adjusting for p-tau, which was found to be associated with GM volumes in distinct anatomic areas. CSF YKL-40, a biomarker of glial inflammation, is associated with a cerebral structural signature distinct from that related to p-tau neurodegeneration at the earliest stages of cognitive decline due to AD.