Association of high alpha-Klotho-levels in CSF with a later onset of cognitive impairment in patients with Parkinson´s disease

Abstract Background: Parkinson's disease (PD) is an age-related condition characterized by substantial phenotypic variability. Consequently, pathways and proteins involved in biological aging, such as the central aging pathway comprising IGF1, alpha-Klotho, FOXO3a, and PPARγ, may potentially influence disease progression. Methods: We examined CSF levels of alpha-Klotho in 471 PD patients. Of the 471 patients, 96 carried a GBA1-variant, while the 375 non-carriers were classified as PD wildtype. Each patient was stratified into a CSF alpha-Klotho tertile group based on the individual level. Kaplan-Meier survival and Cox regression analysis was conducted. Results: Among Parkinson's disease patients, those with the highest tertile of CSF alpha-Klotho levels reached the "disease milestone" of cognitive impairment at a later stage compared to those in the lowest tertile. Conclusions: Our findings suggest that reduced CSF levels of alpha-Klotho are associated with accelerated cognitive decline in PD. This association appears to be predominantly pronounced in PD GBA1 patients.