Associations Between Klotho Levels, KL-VS Heterozygosity and Cognition in Schizophrenia.

Background and hypothesis: The relationship between Klotho and cognitive dysfunction in schizophrenia has been scarcely explored, with a few paradoxical findings. Hence, we aimed to enhance our understanding by testing associations between the functional KL-VS gene variant and circulating protein levels.

Research design: This case-control study included 239 healthy controls and 241 patients with schizophrenia, who were comprehensively characterized by neurocognitive tests and further subtyped into cognitive clusters; cognitively deficient (CD) and cognitively spared (CS), using K-means cluster analysis. Linear regression models were run to assess the main and iinteraction effects of the KL-VS heterozygosity (KL-VS^Het+)/KL levels with confounding variables (disease status and age) on cognitive scores.

Results: There was no main effect of KL-VS^Het+ on the cognitive domains, but the CD cluster exhibited strong negative interactions between disease status and Klotho for executive function at the gene level, KL-VS^Het+ × disease status, β = -.61, P = .043, with comparatively higher effect observed for KL levels, KL levels × disease status, β = -.91, P = .028. There was an opposing positive interaction for response inhibition, KL-VS^Het+ × disease status, limited again to the CD cluster, β = .35, P = .046, with a higher effect at protein levels, KL levels × disease status, β = .72, <.004, though without CD cluster effect.

Conclusions: Overall, these dissociable patterns of association across cognitive domains indicate the need to exert caution over accepting any generalised direction of effect of Klotho at gene or protein level on cognition in schizophrenia.