Konijnenberg Elles, Tomassen Jori, den Braber Anouk, Ten Kate Mara, Yaqub Maqsood, Mulder Sandra D, Nivard Michel G, Vanderstichele Hugo, Lammertsma Adriaan A, Teunissen Charlotte E, van Berckel Bart N M, Boomsma Dorret I, Scheltens Philip, Tijms Betty M, Visser Pieter Jelle
Alzheimer Center Amsterdam, Department of Neurology, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam UMC, Amsterdam, the Netherlands.
Department of Biological Psychology, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands.
Ann Neurol. 2021 May;89(5):987-1000. doi: 10.1002/ana.26048. Epub 2021 Mar 4.
The present work was undertaken to study the genetic contribution to the start of Alzheimer's disease (AD) with amyloid and tau biomarkers in cognitively intact older identical twins.
We studied in 96 monozygotic twin-pairs relationships between amyloid-beta (Aβ) aggregation as measured by the Aβ1-42/1-40 ratio in cerebrospinal fluid (CSF; n = 126) and positron emission tomography (PET, n = 194), and CSF markers for Aβ production (beta-secretase 1, Aβ1-40, and Aβ1-38) and CSF tau. Associations among markers were tested with generalized estimating equations including a random effect for twin status, adjusted for age, gender, and apolipoprotein E ε4 genotype. We used twin analyses to determine relative contributions of genetic and/or environmental factors to AD pathophysiological processes.
Twenty-seven individuals (14%) had an abnormal amyloid PET, and 14 twin-pairs (15%) showed discordant amyloid PET scans. Within twin-pairs, Aβ production markers and total-tau (t-tau) levels strongly correlated (r range = 0.73-0.86, all p < 0.0001), and Aβ aggregation markers and 181-phosphorylated-tau (p-tau) levels correlated moderately strongly (r range = 0.50-0.64, all p < 0.0001). Cross-twin cross-trait analysis showed that Aβ1-38 in one twin correlated with Aβ1-42/1-40 ratios, and t-tau and p-tau levels in their cotwins (r range = -0.28 to 0.58, all p < .007). Within-pair differences in Aβ production markers related to differences in tau levels (r range = 0.49-0.61, all p < 0.0001). Twin discordance analyses suggest that Aβ production and tau levels show coordinated increases in very early AD.
Our results suggest a substantial genetic/shared environmental background contributes to both Aβ and tau increases, suggesting that modulation of environmental risk factors may aid in delaying the onset of AD pathophysiological processes. ANN NEUROL 2021;89:987-1000.
本研究旨在通过认知功能正常的老年同卵双胞胎的淀粉样蛋白和tau生物标志物，探讨阿尔茨海默病（AD）发病的遗传因素。
我们对96对同卵双胞胎进行了研究，分析脑脊液（CSF；n = 126）中β淀粉样蛋白（Aβ）1-42/1-40比值与正电子发射断层扫描（PET，n = 194）所测量的Aβ聚集之间的关系，以及CSF中Aβ生成标志物（β分泌酶1、Aβ1-40和Aβ1-38）和CSF tau之间的关系。使用广义估计方程对标志物之间的关联进行检验，该方程包括双胞胎状态的随机效应，并对年龄、性别和载脂蛋白E ε4基因型进行了调整。我们采用双胞胎分析来确定遗传和/或环境因素对AD病理生理过程的相对贡献。
27名个体（14%）的淀粉样蛋白PET异常，14对双胞胎（15%）的淀粉样蛋白PET扫描结果不一致。在双胞胎对中，Aβ生成标志物与总tau（t-tau）水平高度相关（r范围 = 0.73 - 0.86，所有p < 0.0001），Aβ聚集标志物与181-磷酸化tau（p-tau）水平中度相关（r范围 = 0.50 - 0.64，所有p < 0.0001）。交叉双胞胎交叉性状分析表明，一个双胞胎中的Aβ1-38与另一个双胞胎中的Aβ1-42/1-40比值以及t-tau和p-tau水平相关（r范围 = -0.28至0.58，所有p < 0.007）。Aβ生成标志物的双胞胎对内差异与tau水平差异相关（r范围 = 0.49 - 0.61，所有p < 0.0001）。双胞胎不一致性分析表明，在AD极早期，Aβ生成和tau水平呈现协同升高。
我们的结果表明，存在大量的遗传/共享环境背景因素导致Aβ和tau水平升高，这表明调节环境风险因素可能有助于延缓AD病理生理过程的发作。《神经病学纪事》2021年；89:987 - 1000。
