Background:Identification of new genetic variants that modify Alzheimer’s disease (AD) risk will elucidate novel targets for curbing the disease progression or delaying symptom onset. Objective:To examine whether the functionally advantageous KLOTHO gene KL-VS variant attenuates age-related alteration in cerebrospinal fluid (CSF) biomarkers or cognitive function in middle-aged and older adults enriched for AD risk. Methods:Sample included non-demented adults (N = 225, mean age = 63±8, 68% women) from the Wisconsin Registry for Alzheimer’s Prevention and the Wisconsin Alzheimer’s Disease Research Center who were genotyped for KL-VS, underwent CSF sampling and had neuropsychological testing data available proximal to CSF draw. Covariate-adjusted multivariate regression examined relationships between age group (Younger versus Older; mean split at 63 years), AD biomarkers, and neuropsychological performance tapping memory and executive function, and whether these relationships differed between KL-VS non-carriers (KL-VSNC) and heterozygote (KL-VSHET). Results:In the pooled analyses, older age was associated with higher levels of total tau (tTau), phosphorylated tau (pTau), and their respective ratios to amyloid-β (Aβ)42 (ps ≤ 0.002), and with poorer performance on neuropsychological tests (ps ≤ 0.001). In the stratified analyses, KL-VSNC exhibited this age-related pattern of associations with CSF biomarkers (all ps ≤ 0.001), and memory and executive function (ps ≤ 0.003), which were attenuated in KL-VSHET (ps≥0.14). Conclusion:Worse memory and executive function, and higher tau burden with age were attenuated in carriers of a functionally advantageous KLOTHO variant. KL-VS heterozygosity seems to be protective against age-related cognitive and biomolecular alterations that confer risk for AD.

中文翻译：

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KLOTHO KL-VS 杂合子中与年龄相关的 Tau 负担和认知缺陷减弱

背景：鉴定改变阿尔茨海默病 (AD) 风险的新遗传变异将阐明遏制疾病进展或延迟症状发作的新目标。目的：研究具有功能优势的 KLOTHO 基因 KL-VS 变异体是否会减弱具有 AD 风险的中老年人的脑脊液 (CSF) 生物标志物或认知功能的年龄相关改变。方在脑脊液抽取附近有可用的神经心理学测试数据。协变量调整的多元回归检查了年龄组之间的关系（年轻与年长；63 岁时的平均分裂）、AD 生物标志物和神经心理表现、记忆和执行功能，以及这些关系在 KL-VS 非携带者（KL-VSNC）和杂合子（KL-VSHET）之间是否不同。结果：在汇总分析中，年龄越大，总 tau (tTau)、磷酸化 tau (pTau) 及其与淀粉样蛋白-β (Aβ)42 (ps ≤ 0.002) 的比率越高，并且表现越差神经心理学测试 (ps ≤ 0.001)。在分层分析中，KL-VSNC 表现出这种与 CSF 生物标志物（所有 ps ≤ 0.001）以及记忆和执行功能（ps ≤ 0.003）相关的年龄相关模式，这些在 KL-VSHET 中减弱（ps≥0.14）。结论：在功能有利的 KLOTHO 变体的携带者中，更差的记忆力和执行功能，以及更高的 tau 负荷随着年龄的增长而减弱。