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

Abstract

ImportanceIdentification 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.ObjectivesTo 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 ParticipantsThis 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 MeasuresAssociations 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.ResultsA 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 RelevanceThe 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.

Longevity factor klotho enhances cognition in aged nonhuman primates

“…Notably, systemic administration of KL does not cross the blood-brain barrier as measured by autoradiography 15 and His-tagged protein studies 5 . Human relevance for KL in brain health is supported by studies showing that individuals with elevated KL, due to genetic KLOTHO variation or other reasons, demonstrate better cognition, attenuated neuropathological measures or decreased dementia risk in aging and Alzheimer's disease 3,[16][17][18][19][20][21][22][23][24][25] .…”

Can accelerated ageing models inform us on age‐related tauopathies?

“…It was later reported that Klotho-VS heterozygosity was associated with a lower cross-sectional and longitudinal increase in amyloid-related tau pathology and tau-related memory defects (Neitzel et al, 2021). Echoed with these findings were two recent clinic observations suggesting that higher levels of CSF Klotho were associated with lower CSF Aβ42 and tau burden (total tau and phosphorylated tau; Driscoll et al, 2021;Grøntvedt et al, 2022). In the experimental realm, Klotho-deficient mice display overt phenotypes compared to their wild-type littermates, such as hypogonadism, premature thymic involution, ectopic calcification, impaired bone mineralisation, skin atrophy, hearing loss and neurodegeneration (Kuro-o, 2009).…”