Leveraging large multi-center cohorts of Alzheimer Disease endophenotypes to understand the role of Klotho heterozygosity on disease risk

Two genetic variants (rs9536314 and rs9527025) in the Klotho gene, encoding a transmembrane protein, implicated on longevity and associated with brain resilience during normal aging, were recently shown to be associated with Alzheimer disease (AD) risk in cognitively healthy individuals that are APOE4 carriers. Specifically, the individuals heterozygous for this variant (KL-SV HET+ ), showed lower risk of developing AD. Furthermore, a neuroprotective effect of KL-VS HET+ has been suggested against amyloid burden for cognitively normal individuals. However, inconsistent associations and a smaller sample size of existing studies pose significant hurdles in drawing definitive conclusions. Here, we have performed a well-powered association analysis between KL-VS HET+ and five different AD endophenotypes; brain amyloidosis measured by positron emission tomography (PET) scans (n = 5,541) or cerebrospinal fluid Aβ levels (CSF; n = 5,093), as well as biomarkers associated with tau pathology: the CSF Tau (n = 5,127), phosphorylated Tau (pTau; n = 4,778) and inflammation: CSF soluble triggering receptor expressed on myeloid cells 2 (sTREM2; n = 2,123) levels. Our results found nominally significant associations of KL-VS HET+ status with biomarkers for brain amyloidosis (e.g. CSF Aβ positivity; odds ratio [OR] = 0.67 [95% CI, 0.55-0.78], β = 0.72, P = 0.007) and tau pathology (e.g. biomarker negative for CSF Tau; OR = 0.39 [95% CI, 0.19-0.77], β = -0.94, P = 0.007, and pTau; OR = 0.50 [95% CI, 0.27-0.96], β = -0.68, P = 0.04) in elderly (60-80 years old) individuals that are cognitively normal and APOE4 carriers. Our work supports previous findings and suggests that the KL-VS HET+ on a APOE4 genotype background may exert a protective effect by modulating the Aβ, Tau, and pTau burden and resulting cognitive decline in older controls susceptible to AD. The biological mechanism underlying APOE4 and KL-VS HET+ interaction and the neuroprotective effect of KL-related pathways against amyloid accumulation may warrant future investigation as a target for preclinical pharmacological studies to explore novel AD drug targets.