Parkinson’s disease is widely recognized for its movement symptoms, but for many patients the greatest burden comes from cognitive decline. Difficulties with planning, attention, focus, and decision-making often emerge early, progress relentlessly, and lack effective therapies. Early genetic studies hinted that a common variant in the KLOTHO gene (KL-VS), which modestly raises circulating klotho levels, might also protect cognition in people with Parkinson’s. Klotho is a well-known longevity protein that supports healthy brain aging and synaptic function in model organisms. Yet whether the KL-VS variant association is truly causal, and exactly how klotho might work in the context of Parkinson’s, remains unknown. In a new study published in The Journal of Neuroscience, Dena Dubal and her team turned first to large human cohorts and then to a well-characterized mouse model of the disease to answer these questions.
Human evidence: The KL-VS variant improves executive cognition in early Parkinson’s
Lead author and Parkinson’s expert Nijee Luthra first examined two independent, carefully characterized groups of patients with early-stage Parkinson’s. The choice of these cohorts was strategic because they included drug-naïve patients with early disease, allowing the team to isolate the effects of klotho on cognition before other treatments could confound the results. In both cohorts they assessed executive cognitive function (calculated from visuospatial, verbal fluency, and abstraction measures). After adjusting for age, sex, education, and known genetic risk factors, individuals carrying one copy of the KL-VS variant consistently performed better on executive tasks than non-carriers. The protective effect was specific to executive functions and was not observed for motor symptoms. These results provided human genetic evidence that higher klotho levels can confer cognitive resilience in the setting of Parkinson’s disease.
Elevating klotho in an α-synucleinopathy model
To determine whether increasing klotho could actually cause these benefits, the researchers crossed mice that overexpress human α-synuclein (the protein that misfolds and aggregates in Parkinson’s brains) with mice engineered to produce modestly higher levels of klotho throughout life. This genetic cross created double-transgenic animals that had elevated circulating and brain klotho levels, closely reproducing the effect seen in humans carrying the KL-VS variant.
Strikingly, klotho-overexpressing, α-synuclein mice lived significantly longer than their littermates that carried only the α-synuclein transgene alone. On cognitive testing, the double-transgenics performed markedly better in the Y-maze, a task that measures spatial working memory and is sensitive to hippocampal function. In contrast, testing on open-field, balance beam, and rotarod endurance demonstrated that motor performance did not improve. This dissociation between cognitive and motor outcomes mirrored the human genetic data and reinforced the hypothesis that klotho selectively targets cognitive vulnerabilities in the aging brain rather than providing a general slowdown of disease.
Klotho restores synaptic strength and clears toxic proteins
In mice overexpressing α-synuclein alone, long-term potentiation (LTP, the process by which synapses become stronger and widely considered a cellular basis for learning) was severely impaired in the hippocampus. This synaptic weakness helps explain the memory and cognitive phenotype of this model. Increasing klotho completely restored LTP to levels seen in healthy wild-type mice. Pharmacological experiments using a specific inhibitor showed that this rescue depended on GluN2B-containing NMDA receptors, a subtype of glutamate receptors known to be especially vulnerable to α-synuclein toxicity.
Mechanistic studies showed significantly lower steady-state levels of both total and phosphorylated α-synuclein protein in the double-transgenic mice. Importantly, this klotho-mediated reduction occurred even though the mRNA levels and translation rates of α-synuclein remained unchanged, pointing clearly to improved protein clearance rather than reduced protein production. Further, it was found that the microglia (the brain’s resident immune cells), internalized and degraded α-synuclein more efficiently when klotho was elevated, including recruiting more of the autophagy adaptor protein p62 inside the microglia.
Why this matters for Parkinson’s treatment
This study stands out because it bridges human genetics and mechanistic neuroscience to demonstrate that a single circulating longevity factor can causally protect cognition in a model of Parkinson’s disease. By identifying both the synaptic and clearance pathways through which it acts, it opens concrete avenues for therapeutic development, whether through klotho itself, klotho-boosting drugs, gene therapy, or small molecules that mimic its effects. In the broader field of aging research, the work exemplifies how fundamental mechanisms of resilience identified in healthy longevity can be harnessed to combat age-related neurodegenerative conditions. It suggests that strategies aimed at bolstering the brain’s intrinsic protective systems may succeed where purely disease-specific approaches have fallen short, offering new hope for preserving cognitive health well into old age.
What’s next for the Dubal lab?
The Dubal team will continue to dig deep into the biology of the longevity factor klotho. Injecting klotho peripherally, with a subcutaneous shot, recapitulates the benefits of life-long genetic overexpression, providing a compelling pathway to a new “resilience” treatment for the aging and diseased brain. This raises key questions. Because klotho does not cross the blood-brain barrier, how do peripheral injections enhance brain function? What signals carry klotho’s benefits into the brain? Together, with biotech partners, we are advancing klotho toward human clinical trials. Since cognitive deficits from aging and disease are one of our biggest biomedical challenges, new treatments could be game-changers for human health.