The inactive X: discovering sex genes that influence female vulnerability to Alzheimer's disease

项目摘要 在定义阿尔茨海默病（AD）的两种标志性蛋白质病，b-淀粉样蛋白和tau蛋白中， 一致表明女性比男性表现出更高水平的tau蛋白。这一发现在老年人中得到了很好的表征。 女性，即使是那些被认为是临床正常的，但生物机制驱动这种性别 差异仍然难以捉摸。性激素的变化，无论是由于更年期或激素治疗，可能是一个 影响因素，虽然效果是模棱两可的。性激素不是唯一的性生物成分 可以发挥作用。性染色体构成了女性在生物学上的遗传基础。 区别于男人。特别是X染色体，在AD领域很大程度上被忽视，这是由于 涉及测量和分析的复杂性。女性拥有两条X染色体，这对女性有着深远的影响。 性别特异性与神经退行性疾病的关联。为了避免“过量”的妇女与 X连锁基因来自两条X染色体，其中一条X染色体在整个身体的每个细胞中随机沉默。 然而，这种随机的X失活是不完全的，有些基因逃避了这种失活。人 在女性中，大约30%的X连锁基因在所有组织类型中始终逃脱失活。这些 失活的X逃逸基因已在文献中报道（n=60），许多参与免疫 系统由于这种现象，女性往往表现出更强大的免疫系统， 患有自身免疫性疾病与AD相关，神经炎症，由强大的免疫系统加剧 被认为是脆弱大脑区域病理学的关键早期驱动因素。这些关键的 证据提出了一个从未被解决的创新问题：不活跃的X逃逸基因是否可以被 解释女性易患阿尔茨海默病的关键这种机制是否可以通过 炎症通路因此，在这个创新的建议中，我提出了一个概念新颖的方法， 通过关注“排除”染色体来解决AD病理学中的性别差异。协同 在AD遗传学领域的专家同事，我将采用最新的技术来检查基因组， 转录组学和表观遗传学的影响，作为体内性别差异的驱动因素 β-淀粉样蛋白和tau蛋白的神经成像标记物。这项研究的范围将是无与伦比的，因为我将利用我的 在神经影像学、数据协调和统计学方面的技能，以联合收割机结合三个大型、深表型队列 有b-淀粉样蛋白和tau正电子发射断层扫描神经成像和全基因组样本， 转录组测序（n=900）和血液中的促炎标志物：哈佛衰老大脑研究 （HABS），无症状阿尔茨海默病抗淀粉样蛋白治疗（A4）研究和纵向评估 淀粉样蛋白风险和神经变性（LEARN）研究。我也将证实我在宗教秩序中的发现 研究，记忆和衰老项目（ROS/MAP）和阿尔茨海默病神经成像倡议（ADNI）。 阐明AD风险的性别特异性机制对确定药物靶点具有深远的影响， 还能更好地预测临床试验中男性和女性的药物反应结果。

PROJECT SUMMARY Of the two hallmark proteinopathies, b-amyloid and tau, that define Alzheimer’s disease (AD), studies consistently show that women exhibit higher levels of tau than men. This finding is well-characterized in older women, even those who are considered clinically normal, but the biological mechanism driving this sex difference remains elusive. Sex hormonal changes, either due to menopause or hormone therapy, may be a contributing factor, although effects are equivocal. Sex hormones are not the only sex biological component that could play a role. Sex chromosomes form the genetic foundation by which women are biologically differentiated from men. The X chromosome, in particular, has largely been ignored in the AD field, due to complexities involving measurement and analysis. Women possess two X chromosomes, which has profound implications for sex-specific associations with neurodegenerative disease. To avoid ‘overdosing’ women with X-linked genes coming from two X chromosomes, one X is randomly silenced in each cell throughout the body. This random X inactivation, however, is incomplete, with some genes escaping this inactivation. In human women, approximately 30% of X-linked genes consistently escape inactivation across all tissue types. Of those inactive X escaped genes that have been reported in the literature (n=60), many are involved in the immune system. Due to this phenomenon, women tend to exhibit more robust immune systems and are more likely to suffer from autoimmune diseases. Of relevance to AD, neuroinflammation, exacerbated by robust immune responses, is argued to be a key early driver of pathology in vulnerable brain regions. These key pieces of evidence give rise to an innovative question that has never been tackled: could inactive X escaped genes be the key to explaining female vulnerability to AD pathology? And could this mechanism occur via an inflammatory pathway? As such, in this innovative proposal I put forward a conceptually novel approach to addressing sex differences in AD pathology by focusing on the ‘eXcluded’ chromosome. In collaboration with expert colleagues in the field of AD genetics, I will employ the latest techniques to examine the genomic, transcriptomic, and epigenetic impact of inactive-X escaped genes as a driver of sex differences in in vivo neuroimaging markers of b-amyloid and tau. This study will be unparalleled in its scope, as I will leverage my skills in neuroimaging, data harmonization and statistics to combine three large, deeply-phenotyped cohorts that have b-amyloid and tau positron emission tomography neuroimaging and samples for whole genome and transcriptome sequencing (n=900) and pro-inflammatory markers in blood: the Harvard Aging Brain Study (HABS), the Anti-Amyloid Treatment in Asymptomatic Alzheimer's (A4) study and the Longitudinal Evaluation of Amyloid Risk and Neurodegeneration (LEARN) study. I will also validate my findings in the Religious Orders Study, the Memory and Aging Project (ROS/MAP) and the Alzheimer’s disease Neuroimaging Initiative (ADNI). Elucidating sex-specific mechanisms for AD risk has far-reaching consequences for identifying drug targets, but also better predicting drug response outcomes in men and women in clinical trials.