Relationship of Klotho with cognition and dementia: A systematic review and meta-analysis

Abstract

Background: The protein Klotho, known for its connection to longevity, has attracted growing interest among researchers for its positive effects on the cognitive function and dementia during aging. Nevertheless, the precise correlation between levels of Klotho and cognitive function and dementia remains inadequately elucidated, with conflicting conclusions arising from different studies.

Objective: To conduct a systematic review and Meta-analysis of the relationship between Klotho levels and cognitive function and dementia.

Methods: Klotho-related literature from January 1988 to February 2025 was systematically retrieved from five databases, including PubMed, Web of Science, Cochrane Library, Baidu Academic, and Science Direct. Subsequently, a two-person independent screening process was employed to assess bias risk and evaluate the quality of the literature. Finally, the filtered literature underwent systematic review and meta-analysis.

Results: The meta-analysis, pooling data from 8 studies, involving 6645 subjects, show statistically significant differences in cognitive function scores across Klotho levels [SMD: -1.14; 95 % CI: -2.48 to -0.40, p = 0.007]. Subgroup analyses showed that the positive correlation among α-Klotho, serum Klotho, plasma Klotho and Klotho protein expression levels with cognition and dementia was statistically significant (p = 0.005, 95 % CI: -3.18 to -0.57;p = 0.01, 95 % CI: -5.53 to -0.71;p = 0.0008, 95 % CI: -0.86 to -0.23; p = 0.02, 95 % CI: -2.22 to -0.18). The quality assessment of the ten observational studies showed a low to high level, while the two other randomized controlled trials (RCTs) were at unclear risk of bias.

Limitations: Firstly, the number of included studies was limited, with most being observational and only two RCTs. Additionally, the RCTs were conducted at single research centers with small sample sizes, which may limit the generalizability of the results as they have not been replicated in multiple settings. Secondly, some factors affecting the severity of dementia such as age, gender, years of illness, and medication use may be potential confounding variables. Thirdly, the studies included in the meta-analysis were all observational, resulting in initially low quality of evidence. Finally, the meta-analysis showed a high degree of heterogeneity among the included studies.

Conclusion: There appears to be a significant correlation between Klotho and cognitive function and dementia. In addition, subgroup analyses suggests that α-Klotho, serum Klotho, and plasma Klotho could be important biomarkers of cognitive function and neurodegeneration. However, the limited number of RCTs and the predominance of observational studies in the meta-analysis mean that the evidence quality is relatively low. Further high-quality RCTs are needed to establish a definitive relationship.

Keywords: Biomarker; Cognitive function; Dementia; Klotho; Meta-analysis; Systematic review.