The ventricle-brain volume ratio (VBR), a sign of cerebral atrophy, is a strong predictor of the course of Alzheimer's disease (AD) and a correlation of cognition. Though it is unclear if klotho alters the established link between age-related brain atrophy and cognitive loss, higher levels of the longevity protein have been associated with improved cognition. Thus, this study investigated if the relationship between VBR and cognition is moderated by serum klotho and whether this relationship is different in younger adults (age ≤61.6 years; median split) than in older adults.
The Wisconsin Alzheimer Disease Research Center and the Wisconsin Registry for Alzheimer Prevention provided data for this cross-sectional study, which was conducted between 2009 and 2023. This was a long-term, community-based study conducted at a research facility. Middle-aged and older adults without cognitive impairment who had undergone venipuncture, magnetic resonance imaging, and neuropsychological testing were included in the analysis.
The majority of these individuals had a family history of AD. An enzyme-linked immunosorbent test was used to determine the concentration of serum soluble α-klotho. Composite z scores for immediate learning, executive function, delayed recall, and global cognition were among the outcome measures. Total ventricular volume divided by total brain volume × 100 was used to determine VBR.
The VBR × klotho interaction was significant for the entire sample; individuals with higher serum klotho levels did better on tests measuring executive function and global cognition, but not on tests measuring immediate learning or delayed recall, despite having more brain atrophy. In the younger group, there were no significant interactions between VBR and Klotho.
The VBR × klotho interaction was significant in the older group; individuals with higher circulating klotho levels did better on tests of executive, global cognition, and immediate, but not delayed recall. Overall, the results add to the growing body of research indicating that klotho may have an age-dependent effect on reducing the negative effects of age-related brain and cognitive changes, including dementia.
Source:
Czaplicki, A. M., Frahmand Driscoll, I., Ma, Y., Gaitán, J. M., Bendlin, B. B., Johnson, S. C., Asthana, S., Dubal, D. B., & Okonkwo, O. C. (2026). Serum klotho levels, brain structure, and cognitive performance. JAMA Neurology. https://doi.org/10.1001/jamaneurol.2025.5581
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