Longevity factor klotho and resistance to cognitive deficits in individuals with Parkinson’s disease and in an α-synuclein mouse model

Aging is the primary risk factor for Parkinson's disease (PD) and PD-related cognitive impairment remains a major unmet biomedical challenge. Klotho, a pleiotropic protein, extends lifespan and enhances cognition, but whether it confers resilience to cognitive impairments in PD is unclear. Here, we show that in humans, the KL-VS genetic variant of <i>KLOTHO,</i> linked to higher circulating klotho levels, associated with better executive cognition in individuals with PD across two independent cohorts. To test causality and explore mechanisms, we turned to mouse models. Transgenic elevation of klotho in a mouse model increased lifespan, improved synaptic and cognitive, but not motor, functions in mice, and decreased steady state α-synuclein (α-syn) levels in the brains of male mice expressing wildtype human α-syn. Complementary in vitro studies showed that klotho rescued α-syn-induced deficits in NMDAR-dependent signaling through GluN2B and augmented α-syn microglial-related uptake, suggesting a potential mechanism by which klotho counters PD-related toxicity. Together, these findings indicate that klotho can counteract cognitive deficits related to PD, possibly by modulating α-syn levels - and these findings may be relevant to new therapeutic pathways for PD.<b>Significance statement</b> Klotho is a longevity factor that improves cognition in old mice, Alzheimer's disease model mice, and old nonhuman primates, yet its role Parkinson's disease (PD)-related cognitive impairment remains unclear. Here, we identified an association between a <i>KLOTHO</i> variant and executive cognitive function in PD, a cognitive domain preferentially affected by the disease. To investigate biological mechanisms of klotho, we leveraged an α-synuclein mouse model of PD and found that klotho decreased cognitive deficits, potentially by increasing synaptic plasticity and reducing α-synuclein levels. Together, these findings suggest that klotho modulates PD-related cognitive deficits and highlight klotho-based strategies as promising therapeutic pathways for cognitive impairment in PD and other α-synucleinopathies.