To assess the utility of CSF YKL-40 in monitoring cognitive progression in de novo Parkinson's disease (PD) patients as well as, predicting future cognitive decline, and its investigating potential underlying mechanisms.

85 Eighty-five HCs and 186 PD patients from the PPMI were recruited in this research. Multiple linear regression was used to examine the cross-sectional relationship between YKL-40 and cognitive decline, and mixed effects modeling was used to examine the longitudinal relationship. Mediation analyses were conducted to explore whether tau-related pathology and Aβ pathology mediated the association between cognitive function and YKL-40. Kaplan-Meier and log-rank test were used to compare the cumulative probability risk of cognitive function progression during follow-up.

At baseline, patients with PD had higher levels of CSF YKL-40 than HCs (p = 0.048). Linear regression showed that higher YKL-40 levels were associated with better cognition (HVLT Retention, β = 0.285, p = 0.034) and higher CSF biomarkers levels (T-tau, β = 0.479, p = 0.002; P-tau, β = 0.051, p = 0.002; Aβ42, β = 0.675, p = 0.007). The influence of  YKL-40 on cognition was partially mediated by tau‑related pathology (a maximum of 50.10%) and Aβ pathology (maximum of 40.50%). Longitudinal analysis showed that YKL-40 was negatively correlated with episodic memory (HVLT Total Recall, β = −0.002, p = 0.008), and positively correlated with CSF biomarkers (T-tau, β = 0.003, p = 0.005; P-tau, β = 0.002, p = 0.012). Higher YKL-40 increased the risk of PD-D by 149% (adjusted HR 2.49, p = 0.018).

CSF YKL-40 can be used as an indicator to monitor cognitive decline in patients with recent-onset PD, and CSF YKL-40 may also be a valuable prognostic marker for PD.