Abstract INTRODUCTION Klotho is a longevity‐associated protein with established neuroprotective properties. However, it is unclear how plasma klotho levels relate to Alzheimer's disease (AD) pathologies and cognitive performance. METHODS In this study, we examined the associations between plasma klotho levels and plasma biomarkers, as well as amyloid beta (Aβ) positron emission tomography (PET), tau PET, neurodegeneration, and cognition, in 354 older adults. Stratified association, interaction, and mediation analyses were conducted to elucidate apolipoprotein E ( APOE ) ε4–dependent relationships and potential underlying pathways. RESULTS Higher plasma klotho levels were associated with lower AD‐related biomarkers and cognitive decline in APOE ε4 carriers. Plasma klotho and APOE ε4 exhibited significant or marginal interactions with less abnormal changes in plasma phosphorylated tau217, glial fibrillary acidic protein, neurofilament light chain, Aβ PET, and cognition. These AD‐related biomarkers mediated the protective effect of plasma klotho on cognitive function in APOE ε4 carriers. DISCUSSION This study suggests that plasma klotho is an APOE ε4–dependent protective factor, which may attenuate AD‐related pathology and improve cognitive performance.
Yang et al. (Wed,) studied this question.