KLOTHO-VS heterozygosity, α-klotho protein levels and cognitive performance in Alzheimer’s disease

TL;DR

This study explores how a genetic variant in the KLOTHO gene may be linked to better brain health and memory in Alzheimer's disease.

Contribution

The study investigates the potential neuroprotective role of KLOTHO-VS heterozygosity in Alzheimer’s disease and its interaction with APOE ε4 status.

Findings

KL-VS heterozygosity showed a trend toward lower odds of Alzheimer’s-related cognitive impairment.

KL-VS heterozygotes with aMCI due to AD had better memory performance, especially those with the APOE ε4 allele.

Soluble α-Klotho levels did not differ significantly between groups or correlate with memory performance.

Abstract

KLOTHO-VS (KL-VS) heterozygosity, a variant of the KLOTHO gene, and its encoded protein, α-Klotho, are associated with brain health and show neuroprotective potential against Alzheimer’s disease (AD). We aimed to assess whether KL-VS heterozygosity, cerebrospinal fluid (CSF) and serum soluble α-Klotho (sαKl) levels, would be associated with a lower likelihood of AD and better performance on memory and other cognitive domains in individuals with AD dementia, amnestic mild cognitive impairment (aMCI) due to AD, and cognitively unimpaired controls.

In this cross-sectional study, we analyzed two partially overlapping subsamples derived from 296 participants from the Czech Brain Aging Study. The first subsample included 196 participants with KL-VS haplotype data: 71 with AD dementia, 84 with aMCI due to AD, and 41 cognitively unimpaired controls. The second subsample included 147 participants with CSF and/or serum sαKl measurements, including 58 with AD dementia, 59 with aMCI due to AD, and 30 cognitively unimpaired controls. Diagnoses of aMCI and AD dementia were confirmed by positive CSF biomarkers and/or amyloid PET imaging. Logistic regression assessed how KL-VS heterozygosity influenced the odds of aMCI or dementia due to AD. Linear regression investigated associations between cognitive performance and either KL-VS heterozygosity or CSF/serum sαKl levels. Analysis of variance and analysis of covariance with post-hoc tests were used to compare sαKl levels across study groups.

KL-VS heterozygosity carriers showed a consistent trend towards lower odds of being classified with aMCI and dementia due to AD, with similar patterns in both Apolipoprotein E ε4 (APOE ε4) allele carriers and non-carriers, although none of the associations reached statistical significance despite moderate (rather than small) effect sizes. Among individuals with aMCI due to AD, KL-VS heterozygotes displayed better memory performance (β = 0.61, p = .008), particularly those who also carried the APOE ε4 allele (β = 0.64, p = .042). Results with other cognitive domains were non-significant. No significant differences in sαKl levels were found between study groups, and soluble α-Klotho levels did not associate with memory performance.

KL-VS heterozygosity may be linked to lower likelihood of classification as aMCI or dementia due to AD, and its association with memory might be specific to the aMCI stage of AD and modulated by APOE ε4 status.

The online version contains supplementary material available at 10.1186/s13195-025-01878-5.

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