Highlights
Protective Buffering
In older adults, higher serum klotho levels significantly moderate the negative impact of brain atrophy on global cognition and executive function.
Age-Dependent Effects
The neuroprotective association of klotho appears to be age-dependent, appearing significant in individuals older than 61.6 years, but not in younger cohorts.
Cognitive Resilience
High klotho levels allowed participants to maintain better cognitive performance despite having a higher ventricle-brain volume ratio (VBR), a hallmark of cerebral atrophy.
Background: The Challenge of Brain Atrophy and Cognitive Decline
Cerebral atrophy is an inevitable component of the aging process, yet its clinical manifestation varies significantly across individuals. In the context of Alzheimer’s disease (AD) and related dementias, the ventricle-brain volume ratio (VBR) serves as a robust radiologic marker of neurodegeneration. A high VBR typically correlates with cognitive decline and is a reliable predictor of the transition from mild cognitive impairment to AD dementia.
However, clinical practice often reveals a discrepancy between structural brain health and functional cognitive performance. Some individuals exhibit significant atrophy on magnetic resonance imaging (MRI) yet maintain high levels of cognitive functioning. This phenomenon, often referred to as cognitive resilience, has led researchers to investigate biological factors that might buffer the brain against the functional consequences of structural loss. One such candidate is the longevity protein, klotho.
The Klotho Protein: A Mediator of Longevity and Neuroprotection
Named after the Greek Fate Clotho, who spins the thread of life, klotho is a pleiotropic protein primarily expressed in the kidneys and the choroid plexus of the brain. The soluble form of α-klotho circulates in the blood and cerebrospinal fluid, where it exerts various systemic effects, including the regulation of oxidative stress, insulin signaling, and ion channel activity.
In the central nervous system, klotho is believed to enhance synaptic plasticity by stabilizing N-methyl-D-aspartate (NMDA) receptors and promoting oligodendrocyte maturation. Previous studies have linked higher circulating klotho levels to better cognitive performance in healthy aging populations. However, until recently, it was unclear whether klotho could specifically modify the known adverse association between age-related brain atrophy and cognitive decline.
Study Design and Methodology
To address this gap, researchers conducted a cross-sectional study using data from two major longitudinal cohorts: the Wisconsin Alzheimer Disease Research Center and the Wisconsin Registry for Alzheimer Prevention. The study spanned from 2009 to 2023 and included 308 middle-aged and older adults (mean age 61.3 years; 80% female). Notably, 74% of the participants had a parental history of Alzheimer’s disease, placing them at higher risk for future cognitive impairment.
The researchers utilized a multi-modal approach:
Neuroimaging
MRI was used to calculate the VBR (total ventricular volume divided by total brain volume × 100), providing a quantitative measure of cerebral atrophy.
Biochemical Analysis
Serum soluble α-klotho concentrations were measured via enzyme-linked immunosorbent assay (ELISA).
Neuropsychological Testing
Participants underwent comprehensive testing to produce composite z scores for global cognition, executive function, delayed recall, and immediate learning.
Key Findings: Klotho as a Cognitive Buffer
The results of the study, published in JAMA Neurology, provide compelling evidence for klotho’s role as a moderator of neurodegeneration. Across the entire sample, a significant interaction was found between VBR and klotho levels. Specifically, individuals with higher serum klotho levels performed better on assessments of global cognition and executive function, even when significant brain atrophy was present.
The most striking findings emerged when the data were stratified by age (using a median split of 61.6 years):
The Older Cohort (>61.6 years)
In the older group, the VBR × klotho interaction was highly significant. For these individuals, higher circulating klotho levels were associated with better scores in:
- Global Cognition (P = .01; 95% CI, 0.12-1.06)
- Executive Function (P = .01; 95% CI, 0.19-1.24)
- Immediate Learning (P = .03; 95% CI, 0.06-1.20)
Remarkably, these participants maintained cognitive performance despite having higher VBR, suggesting that klotho acts as a functional buffer against the structural symptoms of aging.
The Younger Cohort (≤61.6 years)
In contrast, the VBR × klotho interactions were not significant in the younger group. This suggests that the neuroprotective benefits of klotho may only become critical once a certain threshold of age-related vulnerability or structural decline is reached.
Cognitive Domains
While global cognition and executive function showed strong interactions, delayed recall did not show a significant relationship with klotho levels. This suggests that klotho may be more influential in maintaining frontal-executive circuits than hippocampal-dependent memory storage in this specific population.
Expert Commentary: Mechanistic Insights and Clinical Implications
The finding that klotho moderates the effect of VBR only in older adults is of particular interest to the scientific community. It suggests that klotho may not prevent atrophy itself, but rather enhances the brain’s ability to compensate for it. This aligns with the “brain maintenance” versus “cognitive reserve” theories of aging. While klotho may contribute to brain maintenance, its primary role in this study appears to be bolstering cognitive reserve.
From a mechanistic standpoint, klotho’s ability to enhance glutamate receptor signaling (specifically the GluN2B subunit of the NMDA receptor) may explain the improvements in executive function and learning. These processes rely heavily on synaptic plasticity and the efficiency of neural transmission across cortical networks.
However, the study is not without limitations. The cross-sectional nature of the data prevents the establishment of a causal relationship. While the findings are robust, longitudinal studies are required to determine if rising or falling klotho levels over time predict the trajectory of cognitive decline. Additionally, the sample was predominantly female and consisted of individuals with a high genetic risk for AD, which may limit the generalizability of the results to broader populations.
Conclusion and Future Directions
The research by Czaplicki et al. underscores the potential of serum klotho as a biomarker for cognitive resilience and a target for therapeutic intervention. If circulating klotho can indeed protect the aging brain from the functional consequences of atrophy, then strategies to increase klotho levels—whether through lifestyle interventions, pharmacological agents, or gene therapy—could represent a new frontier in the prevention of Alzheimer’s disease.
For clinicians, these findings highlight the importance of considering biological modifiers when interpreting neuroimaging results. A patient with visible atrophy on an MRI may not be destined for immediate cognitive failure if other protective factors, such as high klotho levels, are at play. Future research should focus on whether exogenous klotho administration can replicate these protective effects in clinical trials.
References
1. Czaplicki AM, Frahmand Driscoll I, Ma Y, et al. Serum Klotho Levels, Brain Structure, and Cognitive Performance. JAMA Neurol. 2026; doi:10.1001/jamaneurol.2025.5581.
2. Dubal DB, Yokoyama JS, Zhu L, et al. Life extension factor klotho enhances cognition. Cell Rep. 2014;7(4):1065-1076.
3. Yuan L, Zhai L, Geng J, et al. The role of Klotho in the nervous system. Clin Chim Acta. 2021;517:103-110.
