Ali Muhammad, Sung Yun Ju, Wang Fengxian, Fernández Maria V, Morris John C, Fagan Anne M, Blennow Kaj, Zetterberg Henrik, Heslegrave Amanda, Johansson Per M, Svensson Johan, Nellgård Bengt, Lleó Alberto, Alcolea Daniel, Clarimon Jordi, Rami Lorena, Molinuevo José Luis, Suárez-Calvet Marc, Morenas-Rodríguez Estrella, Kleinberger Gernot, Haass Christian, Ewers Michael, Levin Johannes, Farlow Martin R, Perrin Richard J, Cruchaga Carlos
Department of Psychiatry, Washington University School of Medicine, St. Louis, Missouri, United States of America.
Neurogenomics and Informatics Center, Washington University School of Medicine, St. Louis, Missouri, United States of America.
PLoS One. 2022 May 26;17(5):e0267298. doi: 10.1371/journal.pone.0267298. eCollection 2022.
Two genetic variants in strong linkage disequilibrium (rs9536314 and rs9527025) in the Klotho (KL) gene, encoding a transmembrane protein, implicated in longevity and associated with brain resilience during normal aging, were recently shown to be associated with Alzheimer disease (AD) risk in cognitively normal participants who are APOE ε4 carriers. Specifically, the participants heterozygous for this variant (KL-SVHET+) showed lower risk of developing AD. Furthermore, a neuroprotective effect of KL-VSHET+ has been suggested against amyloid burden for cognitively normal participants, potentially mediated via the regulation of redox pathways. However, inconsistent associations and a smaller sample size of existing studies pose significant hurdles in drawing definitive conclusions. Here, we performed a well-powered association analysis between KL-VSHET+ and five different AD endophenotypes; brain amyloidosis measured by positron emission tomography (PET) scans (n = 5,541) or cerebrospinal fluid Aβ42 levels (CSF; n = 5,093), as well as biomarkers associated with tau pathology: the CSF Tau (n = 5,127), phosphorylated Tau (pTau181; 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-VSHET+ 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 positivity 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 cognitively normal participants, 60-80 years old, who are APOE e4-carriers. Our work supports previous findings, suggesting that the KL-VSHET+ on an APOE ε4 genotype background may modulate Aβ and tau pathology, thereby lowering the intensity of neurodegeneration and incidence of cognitive decline in older controls susceptible to AD.
在编码一种跨膜蛋白的Klotho（KL）基因中，有两个处于强连锁不平衡状态的基因变异（rs9536314和rs9527025），它们与长寿相关，且在正常衰老过程中与大脑弹性有关。最近研究表明，在携带APOE ε4的认知正常参与者中，这些变异与阿尔茨海默病（AD）风险相关。具体而言，携带这种变异杂合子（KL - SVHET +）的参与者患AD的风险较低。此外，对于认知正常的参与者，KL - VSHET +可能通过调节氧化还原途径对淀粉样蛋白负荷具有神经保护作用。然而，现有研究结果不一致且样本量较小，这给得出明确结论带来了重大障碍。在此，我们对KL - VSHET +与五种不同的AD内表型进行了一项有力的关联分析；通过正电子发射断层扫描（PET）扫描测量的脑淀粉样变性（n = 5,541）或脑脊液Aβ42水平（CSF；n = 5,093），以及与tau病理相关的生物标志物：脑脊液Tau（n = 5,127）、磷酸化Tau（pTau181；n = 4,778）和炎症：脑脊液髓样细胞上表达的可溶性触发受体2（sTREM2；n = 2,123）水平。我们的研究结果发现，在60 - 80岁、携带APOE ε4的认知正常参与者中，KL - VSHET +状态与脑淀粉样变性生物标志物（如脑脊液Aβ阳性；比值比[OR] = 0.67 [95%可信区间，0.55 - 0.78]，β = 0.72，p = 0.007）和tau病理（如脑脊液Tau生物标志物阳性；OR = 0.39 [95%可信区间，0.19 - 0.77]，β = -0.94，p = 0.007，以及pTau；OR = 0.50 [95%可信区间，0.27 - 0.96]，β = -0.68，p = 0.04）存在名义上显著的关联。我们的研究支持了先前的发现，表明在APOE ε4基因型背景下的KL - VSHET +可能调节Aβ和tau病理，从而降低易患AD的老年对照者的神经变性强度和认知衰退发生率。
