Klotho allele status is not associated with Aβ and APOE ε4–related cognitive decline in preclinical Alzheimer's disease

The longevity gene Klotho (KL), specifically the functional KL-VS variant, has previously been associated with cognition and rates of cognitive decline. This study aimed to determine whether KL-VS associations with cognition were observable in preclinical Alzheimer's disease (AD). The study also aimed to determine whether there was a combined influence of KL-VS, neocortical amyloid-β (Aβ) burden, and carriage of the apolipoprotein E (APOE) ε4 allele on cognitive decline. This study involved 581 Aβ-imaged, cognitively normal older adults, enrolled in the Australian Imaging, Biomarkers and Lifestyle Study of Aging. Linear mixed effects models revealed no significant associations between KL-VS and cognitive decline independently or in combination with Aβ burden and APOE ε4 genotype. Overall, previous associations reported between KL-VS and cognitive decline are not observed at the preclinical stages of AD. Furthermore, the results do not support the hypothesis that KL-VS has a modifying effect on Aβ burden and APOE ε4–driven cognitive decline in preclinical AD.