论文标题：Association of Klotho-VS Heterozygosity With Risk of Alzheimer Disease in Individuals Who Carry APOE4 作者：Michael E. Belloy, Valerio Napolioni, Summer S. Han, Yann Le Guen, Michael D. Greicius 期刊：JAMA Neurology 发表时间：2020/04/13 数字识别码：10.1001/jamaneurol.2020.0414 摘要：ImportanceIdentification of genetic factors that interact with the apolipoprotein e4 (APOE4) allele to reduce risk for Alzheimer disease (AD) would accelerate the search for new AD drug targets.Klotho-VS heterozygosity (KL-VSHET+status) protects against aging-associated phenotypes and cognitive decline, but whether it protects individuals who carryAPOE4from AD remains unclear.ObjectivesTo determine ifKL-VSHET+status is associated with reduced AD risk and β-amyloid (Aβ) pathology in individuals who carryAPOE4.Design, Setting, and ParticipantsThis study combined 25 independent case-control, family-based, and longitudinal AD cohorts that recruited referred and volunteer participants and made data available through public repositories. Analyses were stratified byAPOE4status. Three cohorts were used to evaluate conversion risk, 1 provided longitudinal measures of Aβ CSF and PET, and 3 provided cross-sectional measures of Aβ CSF. Genetic data were available from high-density single-nucleotide variant microarrays. All data were collected between September 2015 and September 2019 and analyzed between April 2019 and December 2019.Main Outcomes and MeasuresThe risk of AD was evaluated through logistic regression analyses under a case-control design. The risk of conversion to mild cognitive impairment (MCI) or AD was evaluated through competing risks regression. Associations with Aβ, measured from cerebrospinal fluid (CSF) or brain positron emission tomography (PET), were evaluated using linear regression and mixed-effects modeling.ResultsOf 36 530 eligible participants, 13 782 were excluded for analysis exclusion criteria or refusal to participate. Participants were men and women aged 60 years and older who were non-Hispanic and of Northwestern European ancestry and had been diagnosed as being cognitively normal or having MCI or AD. The sample included 20 928 participants in case-control studies, 3008 in conversion studies, 556 in Aβ CSF regression analyses, and 251 in PET regression analyses. The genotypeKL-VSHET+was associated with reduced risk for AD in individuals carryingAPOE4who were 60 years or older (odds ratio, 0.75 [95% CI, 0.67-0.84];P = 7.4 × 10−7), and this was more prominent at ages 60 to 80 years (odds ratio, 0.69 [95% CI, 0.61-0.79];P = 3.6 × 10−8). Additionally, control participants carryingAPOE4withKL-VS heterozygosity were at reduced risk of converting to MCI or AD (hazard ratio, 0.64 [95% CI, 0.44-0.94];P = .02). Finally, in control participants who carriedAPOE4and were aged 60 to 80 years,KL-VS heterozygosity was associated with higher Aβ in CSF (β, 0.06 [95% CI, 0.01-0.10];P = .03) and lower Aβ on PET scans (β, −0.04 [95% CI, −0.07 to −0.00];P = .04).Conclusions and RelevanceThe genotypeKL-VSHET+is associated with reduced AD risk and Aβ burden in individuals who are aged 60 to 80 years, cognitively normal, and carryingAPOE4. Molecular pathways associated withKLmerit exploration for novel AD drug targets. TheKL-VS genotype should be considered in conjunction with theAPOEgenotype to refine AD prediction models used in clinical trial enrichment and personalized genetic counseling. 查看更多 所属学科： 生物 医学 神经科学 阅读论文原文作者 药明康德内容团队 几十年来，科学家们已经知道一个基因与阿尔茨海默病风险有着千丝万缕关联——APOE4。携带一个拷贝APOE4的人群，患病风险是其他人群的3倍多；如果携带两个拷贝，风险则飙升近10倍。而根据斯坦福大学医学院团队的最新发现，如果同时携带另一种klotho基因变异，相当一部分APOE4携带者则不会患病。换言之，klotho基因变异可能起到了保护作用，是抵消APOE4影响的候选基因。研究结果近日发表于《美国医学会杂志-神经病学》。这一发现为患者风险识别、药物和疗法研发都提供了新洞见。
约15%的健康人携带APOE4基因变异，在阿尔茨海默病患者中，这一比例高达50% 以上。但从另一个角度而言，并非所有的APOE4携带者都会患病，一些携带者在85岁甚至90岁时都不会有认知障碍症状。是什么因素起到了保护作用？在多年研究中，斯坦福大学记忆障碍中心主任、神经学教授Michael Greicius博士和他的研究团队注意到了klotho基因变异。在动物研究中，血液中klotho蛋白含量高预示着长寿，在人类研究中也发现了类似的证据。携带一个拷贝的klotho基因变异会增加 klotho蛋白的循环水平，可以防止衰老和认知能力下降。那么，这一基因变异与对APOE4携带者的保护作用有关吗？为此，研究团队追踪了超过2万名60岁以上人群的数据，并分析携带APOE4和klotho基因变异与阿尔茨海默氏病的关联。结果支持了他们的猜测。在9000多名60岁以上的APOE4携带人群中，携带一个拷贝的klotho基因变异与阿尔兹海默病风险降低25%相关；在60岁-80岁人群中，保护效应更显著，患病风险降低31%。携带klotho基因变异的人群，发生早期认知障碍的风险也同样更低。在10000多名非ApoE4携带者中，则没有这种关联。对另外近800名受试者的脑脊液或大脑影像学检测结果提示，同时携带klotho基因变异的APOE4携带者，大脑中的β淀粉样蛋白（Aβ）负担也更低——众所周知，Aβ是异常沉积是阿尔茨海默病标志性的一个病理特征。 
▲阿尔茨海默病患者的大脑中，β淀粉样蛋白的异常沉积（褐色斑块）是标志性的病理特征。（图片来源：National Institutes of Health）Greicius博士表示，对APOE4携带者进行klotho基因检测，可以更好地预测他们患阿尔茨海默病的风险。这也带来了新的药物靶标——与klotho基因变异相关的分子途径。此外，很多临床试验通常优先招募患病风险高的APOE4携带者，后续或许应考虑排除携带一个拷贝klotho基因变异的人群，以更好地对比、观察实验性治疗的效果。梅奥诊所神经科学系主席Guojun Bu评论认为，“这是令人振奋的发现，科学家一直在寻找可以抵消APOE4基因不良影响的其他基因，klotho可能正是其中之一，表现为长寿基因对抗短寿基因。”期待对该基因的进一步研究，能为攻克阿尔茨海默病带来好消息！[1] Michael E. Belloy, et al., (2020). Association of Klotho-VS Heterozygosity With Risk of Alzheimer Disease in Individuals Who Carry APOE4. JAMA Neurology, DOI: 10.1001/jamaneurol.2020.0414 [2] Gene variant staves off Alzheimer's in some people, Stanford scientists find. Retrieved Apr 15, 2020, from https://www./pub_releases/2020-04/sm-gvs041020.php [3] Longevity Gene May Protect against a Notorious Alzheimer’s Risk Gene. Retrieved Apr 15, 2020, from https://www./article/longevity-gene-may-protect-against-a-notorious-alzheimers-risk-gene/
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