Shi Liu, Buchanan Colin R, Cox Simon R, Hillary Robert F, Marioni Riccardo E, Campbell Archie, Hayward Caroline, Stolicyn Aleks, Whalley Heather C, Harris Mathew A, Waymont Jennifer, Waiter Gordon, Backhouse Ellen, Wardlaw Joanna M, Steele Douglas, Mcintosh Andrew, Lovestone Simon, Buckley Noel J, Nevado-Holgado Alejo J
Department of Psychiatry University of Oxford Oxford UK.
Lothian Birth Cohorts Group The University of Edinburgh Edinburgh UK.
Alzheimers Dement (Amst). 2021 Sep 27;13(1):e12240. doi: 10.1002/dad2.12240. eCollection 2021.
This study aims to first discover plasma proteomic biomarkers relating to neurodegeneration (N) and vascular (V) damage in cognitively normal individuals and second to discover proteins mediating sex-related difference in N and V pathology.
Five thousand and thirty-two plasma proteins were measured in 1061 cognitively normal individuals (628 females and 433 males), nearly 90% of whom had magnetic resonance imaging measures of hippocampal volume (as N) and white matter hyperintensities (as V).
Differential protein expression analysis and co-expression network analysis revealed different proteins and modules associated with N and V, respectively. Furthermore, causal mediation analysis revealed four proteins mediated sex-related difference in N and one protein mediated such difference in V damage.
Once validated, the identified proteins could help to select cognitively normal individuals with N and V pathology for Alzheimer's disease clinical trials and provide targets for further mechanistic studies on brain sex differences, leading to sex-specific therapeutic strategies.
本研究旨在首先发现认知正常个体中与神经退行性变（N）和血管（V）损伤相关的血浆蛋白质组学生物标志物，其次发现介导N和V病理学中性别差异的蛋白质。
对1061名认知正常个体（628名女性和433名男性）的5032种血浆蛋白进行了检测，其中近90%的个体进行了海马体积（作为N）和白质高信号（作为V）的磁共振成像测量。
差异蛋白表达分析和共表达网络分析分别揭示了与N和V相关的不同蛋白质和模块。此外，因果中介分析显示，四种蛋白质介导了N中的性别差异，一种蛋白质介导了V损伤中的性别差异。
一旦得到验证，所鉴定的蛋白质可有助于为阿尔茨海默病临床试验选择具有N和V病理学的认知正常个体，并为脑性别差异的进一步机制研究提供靶点，从而制定针对性别的治疗策略。
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