Preserved olfaction unmasks choroid plexus–related cognitive risk in Parkinson’s disease

Background Choroid plexus volume (CPV) has been associated with cognitive impairment in Parkinson’s disease (PD), particularly frontal-executive dysfunction, whereas olfactory dysfunction is linked to cognitive deterioration and may reflect greater α-synuclein involvement. Whether olfactory status modifies the association between CPV and cognitive outcomes remains unclear. Methods We analyzed 718 participants with early-stage PD followed for up to 10 years. Baseline CPV was derived from structural MRI. Hyposmia was defined as an age- and sex-adjusted University of Pennsylvania Smell Identification Test percentile ≤ 15. Kaplan–Meier and multivariable Cox models were used to examine incident cognitive milestone (CogM), including a CPV × olfactory status interaction. CPV was standardized to 1-SD units. Multiple sensitivity analyses assessed robustness. Results Among 709 participants with olfactory data, 502 (70.8%) had hyposmia. Ten-year CogM-free survival was 59.4%. The primary Cox analysis included 680 participants and 173 CogM events. Among participants with normosmia, each 1-SD increase in CPV was associated with higher CogM risk (HR = 1.63, 95% CI 1.20–2.22, P = 0.002). Hyposmia was associated with higher CogM risk at the mean CPV level (HR = 1.91, 95% CI 1.23–2.97, P = 0.004). The CPV × hyposmia interaction was significant (HR = 0.62, 95% CI 0.43–0.88, P = 0.008); the CPV association was absent in participants with hyposmia (HR = 1.01, 95% CI 0.83–1.22, P = 0.950). Findings were consistent across sensitivity analyses. Conclusion Olfactory status modified the association between CPV and cognitive outcomes in early PD. Larger CPV was associated with higher CogM risk in participants with preserved olfaction, but not in those with hyposmia. These findings warrant validation in independent cohorts.