Is Klotho associated with cognitive and motor decline in Parkinson’s disease? A systematic review and meta-analysis

Abstract

Background: Klotho is an anti-aging protein with demonstrated neuroprotective properties in preclinical models of Parkinson's disease (PD). However, the relationship between Klotho levels and clinical outcomes in human PD remains unclear. Objective: To examine associations between Klotho levels and cognitive/motor function in PD patients. Methods: We conducted a systematic review and meta-analysis following PRISMA guidelines (PROSPERO: CRD420251182721). We searched PubMed, Scopus, Embase, and Cochrane Lib through Oct 2025. Studies reporting Klotho protein levels (serum or cerebrospinal fluid) in PD patients with cognitive or motor outcomes were included. Case reports, letters, editorials, reviews without original data, and animal studies were excluded. Correlation coefficients were pooled using random-effects models with Fisher's z-transformation. Quality was assessed using ROBINS-I and GRADE frameworks. Analyses were performed in R. Results: 4 studies met the inclusion criteria. Meta-analysis of three studies (621 PD participants) revealed a small but statistically significant positive correlation between Klotho levels and global cognitive function (Fisher's z = 0.137, 95% CI [0.007, 0.266], p = 0.039; back-transformed r = 0.136), with moderate heterogeneity (I² = 49%). Evidence regarding motor symptoms was inconsistent, and PD-control comparisons yielded heterogeneous results. GRADE assessment rated certainty of evidence as very low primarily due to observational designs, small samples sizes, and residual confounding. Conclusion: Higher Klotho levels are associated with better cognitive performance in PD, suggesting Klotho may reflect cognitive resilience rather than neurodegenerative burden. However, very low certainty of evidence precludes clinical application. Good longitudinal studies with standardized assays and comprehensive adjustment for confounders are needed.