Elevated circulating cathepsin S levels are associated with cognitive decline and neurodegeneration in a cohort of patients reporting memory complaints

BackgroundAs a member of the cysteine protease family, cathepsin S has been implicated in the pathogenesis of various diseases, including Alzheimer's disease (AD), primarily by promoting inflammation.ObjectiveCurrent evidence regarding the role of cathepsin S primarily comes from animal studies. This study aims to explore the clinical relevance of cathepsin S in AD.MethodsIn a cohort of older adults aged 60 or above with memory complaints, we examined baseline plasma levels of cathepsin S and assessed their association with cognitive decline and biomarkers of neurodegeneration during a 36-month follow-up.ResultsPlasma levels of cathepsin S were significantly higher in individuals experiencing longitudinal cognitive decline compared to those without cognitive decline. Furthermore, plasma levels of cathepsin S were associated with declines in Mini-Mental State Examination (MMSE) scores and increases in neurofilament light and pTau181 levels. Higher plasma cathepsin S levels were linked to an increased risk of longitudinal cognitive decline (decrease in MMSE scores of 3 or more), adjusting for age, sex, education, <i>APOE</i> genotype, alcohol consumption, smoking, and comorbidities.ConclusionsThis study provides additional evidence supporting the potential role of cathepsin S in the pathogenesis of AD from a clinical perspective.