Associations of KLOTHO-VS heterozygosity and α-Klotho protein with cerebrospinal fluid Alzheimer's disease biomarkers

Background<i>KLOTHO</i>-VS heterozygosity (<i>KL</i>-VSHET) and soluble α-Klotho (sαKl) protein interfere with Alzheimer's disease (AD) pathophysiology, but the specific relationships remain unclear. This study explored these associations across the AD continuum, focusing on core AD biomarkers and markers of neurodegeneration, neuroinflammation, and synaptic dysfunction.ObjectiveWe investigated whether 1) <i>KL</i>-VSHET is associated with lower AD biomarker burden (Aβ₄₂, Aβ_42/40 ratio, P-tau181, T-tau) and neurodegeneration (NfL); 2) sαKl relates to AD biomarkers, neurodegeneration (NfL), neuroinflammation (GFAP), and synaptic dysfunction (Ng); 3) associations vary by <i>APOE</i> ε4 status and clinical subgroup.MethodsParticipants (n = 223) were categorized as cognitively healthy (n = 38), aMCI-AD (n = 94), and AD dementia (n = 91). <i>KLOTHO</i> genotyping was available for 128 participants; 138 had cerebrospinal fluid (CSF) and serum sαKl measurements; and 42 had both. Multiple linear regression evaluated associations between <i>KL</i>-VSHET, sαKl levels, and biomarkers, stratified by <i>APOE</i> ε4 status and clinical subgroup.ResultsOverall, the associations between <i>KL</i>-VSHET and higher CSF Aβ₄₂ and Aβ_42/40 ratio were non-significant (<i>p</i>s ≥ 0.059) except when restricted to <i>APOE</i> ε4 carriers only (β = 0.11, <i>p </i>= 0.008 and β = 0.16, <i>p </i>= 0.033, respectively). Within clinical subgroups, <i>KL</i>-VSHET was positively associated with Aβ_42/40 ratio only in aMCI-AD (β = 0.23, <i>p </i>= 0.034). No significant associations were observed between <i>KL</i>-VSHET and tau biomarkers or NfL. For sαKl, associations with biomarkers were non-significant except for a negative association of serum sαKl with P-tau181 in aMCI-AD (β = -0.25, p = 0.036) and a positive association with Aβ_42/40 ratio in <i>APOE</i> ε4 non-carriers (β = 0.24 p = 0.047).Conclusions<i>KL</i>-VSHET may help protect against amyloid pathology, particularly in the presence of <i>APOE</i> ε4, and regardless of <i>APOE</i> status in aMCI-AD.