Study: Association of klotho protein levels and KL-vs heterozygosity with Alzheimer

Klotho protein levels protect against cognitive decline in Alzheimer’s patients

soon JAMA Network Open In the study, researchers compare Klotho protein levels in both cerebrospinal fluid (CSF) and plasma samples of healthy individuals and patients diagnosed with different stages of Alzheimer’s disease (AD).

Studies: Association with Alzheimer’s disease and amyloid and tau burden versus klotho protein levels and KL-heterozygosity. Image Credit: ART-ur/


Klotho transmembrane protein is expressed primarily in the kidneys and the choroid plexus in the brain. Absence of this protein in the brain klotho knockout mice led to cognitive deficits, premature death, and synaptic loss. Conversely, overexpression of the Klotho protein in mice is associated with a long lifespan, improved cognitive function, and reduced age-related phenotypes.

this KL-VS The haplotype in the Klotho gene typically consists of six missense variants. KL-VS Heterozygosity leading to higher Klotho levels in the body is associated with a longer life expectancy, higher cortical volume, improved cognition, and lower amyloid-associated tau pathology in patients diagnosed with AD.

Despite the documented protective effects associated with Klotho protein, there remains a lack of data on how Klotho concentrations may change in AD patients. In one study, researchers found that CSF Klotho levels decreased with age and were higher in healthy older individuals compared to Alzheimer’s patients. Also, lower plasma Klotho levels were associated with lower Mini-Mental State Examination (MMSE) scores and a higher risk of vascular dementia, but not with late-onset Alzheimer’s disease.

about the study

From January 1, 2009 to December 31, 2018, 243 participants were selected for the current study; of these, 117 served as healthy controls, 102 were considered patients with mild cognitive impairment due to AD (AD-MCI), and 24 patients diagnosed with dementia due to AD (AD-dementia).

Cognitive testing, including neurological examination, blood screening, CSF collection, and MMSE, was performed for all study participants.

Study findings

Compared with both AD-MCI and AD-dementia patients, healthy controls had the highest median Klotho levels in CSF samples. Notably, Klotho protein levels in the CSF of AD patients decreased as disease severity increased. A weak but significant correlation was observed between CSF Klotho levels and both age and MMSE scores.

Previous studies have shown that individuals with APOE4 allele and heterozygous KL-VS exhibited reduced amyloid burden and risk of AD. However, in the current study APOE4 The allele had no significant effect on CSF Klotho concentrations in any of the study cohorts, regardless of gender.

Further analysis of CSF AD biomarkers, including Aβ42, T-tau and P-tau, showed that CSF Klotho levels had a significant positive association with Aβ42 levels in CSF. Comparatively, a significantly negative correlation was observed between CSF Klotho levels and both T-tau and P-tau levels in CSF. Thus, Klotho protein levels may reflect cognitive function, with lower CSF Klotho levels potentially indicative of a more rapid and significant cognitive decline among patients with AD.

heterozygous KL-VS individuals were associated with significantly higher CSF Klotho levels compared with non-carriers in the AD group; however, this was not observed in the AD-dementia group.

KL-VS heterozygosity had no significant effect on Aβ42, T-tau and P-tau levels in CSF samples of any group.

Correlations with plasma Klotho levels

both APOE4 status and gender had no significant effect on plasma Klotho concentrations. However, a significant negative correlation was detected between plasma Klotho levels and age.

However, a significant negative correlation was detected between plasma Klotho levels and T-tau levels in CSF.

KL-VS Heterozygotes were more likely to have higher median plasma Klotho levels compared to non-carriers. This correlation was significantly different among AD patients. KL-VS heterozygous carriers displaying higher Klotho levels in plasma compared to non-carriers; however, this difference was significant when only the AD-HBB group was considered.


Taken together, the study findings suggest that greater amounts of Klotho protein in CSF are associated with reduced levels of CSF amyloid and tau burden. These differences were independent of both. KL-VS heterozygosity and APOE4 shows the status so KL-VS haplotype may not be indicative of AD pathogenesis to the same extent as Klotho protein levels.

More research is needed to better understand the mechanisms responsible for decreased Klotho levels during aging, particularly in patients with AD. In addition, therapeutic approaches that could potentially increase Klotho levels should also be explored.

Journal reference:

  • Grøntvedt, GR, Sando, SB, Lauridsen, C., et al. (2022). Association with Alzheimer’s disease and amyloid and tau burden versus klotho protein levels and KL-heterozygosity. JAMA Network Open. doi:10.1001/jamanetworkopen.2022.43232

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