Abstract
BackgroundKallikrein 6 (KLK6) is known to be an age-related protease expressed at high levels in the central nervous system. It was previously shown to be involved in proteolysis of extracellular proteins implicated in neurodegenerative diseases such as Alzheimer’s disease (AD), prompting validation of KLK6 as a potential biomarker of disease. However, analyses of both plasma and cerebrospinal fluid (CSF) levels of KLK6 in patients with AD have been inconclusive. We present a detailed analysis of KLK6 in plasma and CSF in two separate cohorts in a cross-sectional and a longitudinal clinical setting.MethodsThe cross-sectional cohort included control subjects without dementia and patients with AD, and the longitudinal cohort included patients with MCI and patients with AD followed over a 2-year period. Plasma and CSF levels of KLK6 were quantified by use of a previously developed and validated enzyme-linked immunosorbent assay. Statistical analyses were performed to compare KLK6 levels between diagnostic groups and to identify potential associations between KLK6 level, age, apolipoprotein E (APOE) genotype, total apoE level and the classical CSF AD biomarkers.ResultsIn the cross-sectional setting, KLK6 levels in plasma but not in CSF were significantly higher in the AD group than in control subjects. CSF but not plasma KLK6 levels were positively correlated with age in both the cross-sectional and longitudinal settings. In both cohorts, the CSF KLK6 levels were significantly and positively correlated with the CSF levels of core AD biomarkers. Total plasma and CSF apoE levels were positively associated with KLK6 in the cross-sectional study. Finally, during the 2-year monitoring period of the longitudinal cohort, CSF KLK6 levels increased with disease progression over time in the investigated patient groups.ConclusionsIn two separate cohorts we have confirmed the previously reported correlation between age and CSF levels of KLK6. Increased plasma KLK6 levels in patients with AD with a more advanced disease stage suggest KLK6 as a potential biomarker in patients with AD with more severe dementia. Significant correlations between KLK6 levels and core CSF AD biomarkers suggest molecular links between KLK6 and AD-related pathological processes.
Highlights
Kallikrein 6 (KLK6) is known to be an age-related protease expressed at high levels in the central nervous system
No significant difference in age was found between the patient groups included in cohort 2, but the mild cognitive impairment (MCI)-Alzheimer’s disease (AD) and AD-AD groups differed significantly in age compared with control subjects (p = 0.0036 for MCI who developed AD (MCI-AD) and p = 0.0228 for AD-AD, after Bonferroni correction for six comparisons)
We further show that cerebrospinal fluid (CSF) KLK6 levels were not useful for identifying patients with MCI transitioning into an AD diagnosis over the 24-month period investigated
Summary
Kallikrein 6 (KLK6) is known to be an age-related protease expressed at high levels in the central nervous system. It was previously shown to be involved in proteolysis of extracellular proteins implicated in neurodegenerative diseases such as Alzheimer’s disease (AD), prompting validation of KLK6 as a potential biomarker of disease. Analyses of both plasma and cerebrospinal fluid (CSF) levels of KLK6 in patients with AD have been inconclusive. Owing to the heterogeneity in the age at onset of sporadic AD, future efforts need to address whether a different or additional set of biomarkers would be more appropriate for patients with AD developing disease at a younger or older age
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