Sex‐specific associations of cerebrospinal fluid YKL‐40 with white matter hyperintensities over a 7‐year follow‐up period

Abstract

AbstractBackgroundWomen have a higher prevalence of Alzheimer’s disease (AD), but the underlying reason remains unknown. White matter damage is common in AD and partially attributed to inflammation. Animal models suggest that neuroinflammation with advanced age may differ between sexes, so we assessed whether sex modified associations between neuroinflammation assessed with cerebrospinal fluid (CSF) chitinase 3‐like 1 protein (YKL‐40) and white matter damage in older adults.MethodVanderbilt Memory and Aging Project participants (n = 152, baseline age 73±7 years, 33% female) underwent lumbar puncture at study entry and brain magnetic resonance imaging (MRI) serially over a 7‐year period (mean follow‐up = 5.5 years). CSF YKL‐40 was quantified using an enzyme‐linked immunosorbent assay. MRI T2‐FLAIR was used to quantify total and lobar white matter hyperintensities (WMHs) at each timepoint. Ordinary least squares regression and linear mixed‐effects models related baseline CSF YKL‐40 to baseline and longitudinal WMHs, adjusting for baseline age, sex, race/ethnicity, education, modified Framingham Stroke Risk Profile, cognitive status, apolipoprotein‐e4 status, and intracranial volume. Longitudinal models adjusted for follow‐up time. Models were repeated with a sex interaction.ResultIn main models, CSF‐YKL‐40 was cross‐sectionally unrelated to total and all lobar WMHs (p‐values>0.20) or longitudinal WMH progression (p‐values>0.06). However, CSF YKL‐40 cross‐sectionally interacted with sex on total, frontal, and parietal lobe WMHs (p‐values<0.05). In stratified models, higher CSF YKL‐40 levels related to greater WMH burden in the frontal (b = 0.005, p = 0.04), parietal (b = 0.005, p = 0.02), temporal (b = 0.003, p = 0.01), and occipital lobes (b = 0.003, p = 0.02) in females only. In longitudinal models, CSF YKL‐40 interacted with sex on temporal lobe WMH progression (p = 0.01), such that higher CSF YKL‐40 at study entry was associated with progression of temporal lobe WMHs over time in females only (b = 0.002, p = 0.003).ConclusionHigher levels of neuroinflammation, reflected by higher levels of CSF YKL‐40, are associated with greater WMHs cross‐sectionally and progression over time in females only. Longitudinally, this effect is specific to the temporal lobe, where AD neuropathology originates. Neuroinflammation may be a key, sex‐specific etiology of temporal lobe white matter damage in females. Additional research is needed to characterize the role of this damage in cognitive decline.FundingIIRG‐08‐88733, R01‐AG034962, R01‐AG056534, K24‐AG046373, P20‐AG068082