Altered dynamic functional connectivity of the language network associated with electronegative L5 in patients with mild cognitive impairment.

Language impairment is increasingly recognized as an early marker of neurodegeneration in mild cognitive impairment (MCI). L5, an electronegative subfraction of low-density lipoprotein cholesterol, has been implicated in both vasculopathy and neurodegenerative processes, positioning it as a potential contributing factor to MCI pathology. This study investigates alterations in the connectivity and dynamics of core language networks and aims to elucidate the diverse pathophysiological processes underlying language decline. We enrolled 22 patients with clinically defined MCI and 30 cognitively normal individuals. Cognitive function was assessed using the Cognitive Abilities Screening Instrument. Serum L5 levels were quantified by anion-exchange chromatography. Resting-state functional magnetic resonance imaging (MRI) was used to evaluate functional connectivity and Granger causal interactions within predefined language-related regions. Correlation analyses and prespecified multivariable linear regression models were performed to examine the independent associations among serum L5 percentage (L5%), language performance, and functional connectivity, with sensitivity analyses based on Cook's distance to assess the robustness of the findings. Compared to normal cognitive group, the MCI group showed significantly reduced functional connectivity in key language areas. Directional interaction between the left orbital inferior frontal cortex and left superior temporal gyrus was notably altered in the MCI group. In those with MCI, left orbital inferior frontal functional connectivity was inversely correlated with L5% (r = -0.43, 95% CI = -0.73 to 0.01, p = .04). These associations remained significant after adjustment for hypertension and apolipoprotein E ε4 status. This study provides novel evidence suggesting that L5 is associated with dysfunction within language-related neural networks and may serve as a candidate biomarker reflecting language impairment in MCI.