Klotho-VS heterozygosity (KL-VShet) is associated with reduced risk of Alzheimer's disease (AD). However, whether KL-VShet is associated with lower levels of pathologic tau, i.e. the key AD pathology driving neurodegeneration and cognitive decline, is unknown. Here, we assessed the interaction between KL-VShet and levels of beta-amyloid, a key driver of tau pathology, on the levels of PET-assessed neurofibrillary tau in 354 controls and patients within the AD continuum. KL-VShet showed lower cross-sectional increase in tau-PET per unit increase in amyloid-PET when compared to that of non-carriers. This effect of KL-VShet on tau-PET showed a tendency to be stronger in Klotho mRNA-expressing brain regions mapped onto a gene expression atlas. KL-VShet was related to better memory functions and this association was mediated by lower tau-PET. Amyloid-PET levels did not differ between KL-VShet carriers versus non-carriers. Together, our findings provide evidence for a protective role of KL-VShet against tau pathology and tau-related memory impairments in elderly humans at risk of AD dementia.

中文翻译：

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KL-VS杂合性与阿尔茨海默氏病中tau积累减少和记忆障碍降低有关

Klotho-VS杂合性（KL-VShet）与降低阿尔茨海默氏病（AD）的风险有关。然而，尚不清楚KL-VShet是否与较低水平的病理tau关联，即驱动神经变性和认知能力下降的关键AD病理。在这里，我们评估了354名对照组和AD连续性患者中PET评估的神经原纤维tau的水平，评估了KL-VShet与tau病理的关键驱动因素β-淀粉样蛋白之间的相互作用。与非载体相比，KL-VShet的淀粉蛋白-PET单位增加时，tau-PET的横截面增加较低。KL-VShet对tau-PET的作用显示出在映射到基因表达图谱上的表达Klotho mRNA的大脑区域更强的趋势。KL-VShet与更好的记忆功能有关，这种关联是由较低的tau-PET介导的。KL-VShet携带者与非携带者之间的淀粉样PET水平没有差异。在一起，我们的研究结果提供了证据证明KL-VShet对患有AD痴呆风险的老年人的tau病理学和tau相关记忆障碍有保护作用。