Circulating klotho is elevated in cerebrospinal fluid, but not serum, among KLOTHO KL‐VS allele carriers at risk for Alzheimer’s disease

Abstract

AbstractBackgroundThe klotho protein supports brain health and is encoded by the KLOTHO gene. The KL‐VS allele modulates klotho protein secretion and function, but it is unknown how KL‐VS genotype affects circulating klotho levels in blood and cerebrospinal fluid (CSF) among people at risk for AD.Methods1112 cognitively intact participants from the Wisconsin Registry for Alzheimer’s Prevention and Wisconsin Alzheimer’s Disease Research Center underwent genotyping for KLOTHO KL‐VS (non‐carrier: KL‐VSNC; heterozygote: KL‐VSHET; homozygote: KL‐VSHOM) and APOE4 alleles. 1098 participants underwent venipuncture and 183 underwent lumbar puncture. Circulating klotho was measured by ELISA in serum and/or CSF. Linear regression adjusted for age and sex tested the effect of KL‐VS genotype on klotho in serum or CSF. In a subset of 169 participants with both serum and CSF data, linear regression adjusted for time between specimen collections tested the effect of specimen source on klotho level.ResultsVisual inspection for outliers excluded four high serum klotho values (range 2461.5–4171.3 pg/mL; two KL‐VSNC, one KL‐VSHET, one KL‐VSHOM); no CSF values were excluded. The mean participant age was 62.4 ± 6.6 and education was 15.8 ± 2.7 years. The majority were female (69.4%), White (92.6%), and had family history of dementia (72.6%), and 38.1% were APOE4 carriers. KL‐VS genotype distribution was 73.1% KL‐VSNC, 25.2% KL‐VSHET, and 1.7% KL‐VSHOM. Mean serum klotho in KL‐VSNC was 800.8 ± 252.8 pg/mL and was not different in KL‐VSHET (b=17.7, SE=17.5, p=.31) or KL‐VSHOM (b=84.0, SE=58.1, p=.15). Mean CSF klotho in KL‐VSNC was 932.2 ± 153.2 pg/mL and was significantly higher in KL‐VSHET (b = 225.8, SE = 25.1, p< .001) and KL‐VSHOM (b=327.8, SE=75.5, p< .001). Mean CSF klotho was significantly higher than serum klotho in the entire subset (b=162.8, SE=25.9), p< .001) and within each KL‐VS genotype (p’s< .05).ConclusionsIn adults at risk for AD, CSF klotho is elevated in heterozygotic and homozygotic carriers of the KLOTHO KL‐VS allele. Serum levels are lower than CSF and did not differ by genotype. Klotho specimen source should be considered in analyses of circulating klotho on brain health.