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. 2022 Nov 1;5(11):e2243232.
doi: 10.1001/jamanetworkopen.2022.43232.

Association of Klotho Protein Levels and KL-VS Heterozygosity With Alzheimer Disease and Amyloid and Tau Burden

Gøril Rolfseng Grøntvedt  1   2   3 , Sigrid Botne Sando  1   2   3 , Camilla Lauridsen  1 , Geir Bråthen  1   2   3 , Linda R White  2 , Øyvind Salvesen  4 , Dag Aarsland  5   6 , Erik Hessen  7   8 , Tormod Fladby  8   9 , Knut Waterloo  10 , Katja Scheffler  1   2   3
Affiliations

Association of Klotho Protein Levels and KL-VS Heterozygosity With Alzheimer Disease and Amyloid and Tau Burden

Gøril Rolfseng Grøntvedt et al. JAMA Netw Open. .

Abstract

Importance: Identification of proteins and genetic factors that reduce Alzheimer disease (AD) pathology is of importance when searching for novel AD treatments. Heterozygosity of the KL-VS haplotype has been associated with reduced amyloid and tau burden. Whether this association is mediated by the Klotho protein remains unclear.

Objectives: To assess concentrations of Klotho in cerebrospinal fluid (CSF) and plasma among cognitively healthy controls and patients with AD and to correlate these findings with KL-VS heterozygosity status and amyloid and tau burden.

Design, setting, and participants: This case-control study combined 2 independent case-control AD cohorts consisting of 243 referred patients with AD and volunteer controls recruited from January 1, 2009, to December 31, 2018. Klotho levels were measured in CSF and plasma and correlated with KL-VS heterozygosity status and levels of CSF amyloid-β 42 (Aβ42), total tau, and phosphorylated tau. Statistical analysis was performed from January 1, 2021, to March 1, 2022.

Main outcomes and measures: Associations of Klotho levels in CSF and plasma with levels of CSF biomarkers were analyzed using linear regression. Association analyses were stratified separately by clinical groups, APOE4 status, and KL-VS heterozygosity. Pearson correlation was used to assess the correlation between CSF and plasma Klotho levels.

Results: A total of 243 participants were included: 117 controls (45 men [38.5%]; median age, 65 years [range, 41-84 years]), 102 patients with mild cognitive impairment due to AD (AD-MCI; 59 men [57.8%]; median age, 66 years [range, 46-80 years]), and 24 patients with dementia due to AD (AD-dementia; 12 men [50.0%]; median age, 64.5 years [range, 54-75 years]). Median CSF Klotho levels were higher in controls (1236.4 pg/mL [range, 20.4-1726.3 pg/mL]; β = 0.103; 95% CI, 0.023-0.183; P = .01) and patients with AD-MCI (1188.1 pg/mL [range, 756.3-1810.3 pg/mL]; β = 0.095; 95% CI, 0.018-0.172; P = .02) compared with patients with AD-dementia (1073.3 pg/mL [range, 698.2-1661.4 pg/mL]). Higher levels of CSF Klotho were associated with lower CSF Aβ42 burden (β = 0.519; 95% CI, 0.201-0.836; P < .001) and tau burden (CSF total tau levels: β = -0.884; 95% CI, 0.223 to -0.395; P < .001; CSF phosphorylated tau levels: β = -0.672; 95% CI, -1.022 to -0.321; P < .001) independent of clinical, KL-VS heterozygosity, or APOE4 status. There was a weak correlation between Klotho CSF and plasma levels among the entire cohort (Pearson correlation r = 0.377; P < .001).

Conclusions and relevance: The findings of this case-control study suggest that Klotho protein levels were associated with clinical stages of AD, cognitive decline, and amyloid and tau burden and that these outcomes were more clearly mediated by the protein directly rather than the KL-VS heterozygosity variant. When selecting individuals at risk for clinical trials, the Klotho protein level and not only the genetic profile should be considered.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Fladby reported receiving personal fees from Biogen and Novo Nordisk outside the submitted work. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Cerebrospinal Fluid (CSF) Klotho Levels in the Clinical Groups
This violin plot shows concentrations of Klotho in CSF measured by commercially available human soluble α-Klotho assay enzyme-linked immunosorbent assy kit in different clinical groups. AD indicates Alzheimer disease; AD-MCI, AD with mild cognitive impairment; and CN, cognitively healthy controls.
Figure 2.
Figure 2.. Scatterplot of Cerebrospinal Fluid (CSF) Klotho Levels and Age in the Clinical Groups
This scatterplot shows logarithmic-transformed concentrations of Klotho in CSF and age in different clinical groups. AD-MCI indicates Alzheimer disease with mild cognitive impairment; and CN, cognitively healthy controls.
Figure 3.
Figure 3.. Scatterplot of Cerebrospinal Fluid (CSF) Klotho and Core Alzheimer Disease (AD) Biomarkers in CSF at Baseline in the Clinical Groups
This scatterplot shows logarithmic-transformed concentrations of Klotho in CSF and core CSF AD biomarkers in different clinical groups. Aβ42 indicates amyloid-β 42; AD-MCI, AD with mild cognitive impairment; CN, cognitively healthy controls; P-tau, phosphorylated tau; and T-tau, total tau.
See this image and copyright information in PMC

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