How women’s reproductive life-history relates to cognitive decline and neuropathology in Alzheimer’s disease and related dementias

项目总结 迫切需要了解一生中可能导致性行为和性别的状况 阿尔茨海默病和相关痴呆(ADRD)病因的差异。我们关注的是生育史， 对特定性别的健康产生影响的最根本因素。妊娠和哺乳期是高血压的敏感期。 人类母亲以及其他哺乳动物的可塑性。在这些生命阶段，永久的、重新组织的 包括大脑在内的各种生理系统都会产生影响。因此，有可能女性的 生殖模式改变了一生中神经发病所涉及的风险和机制。我们 都受到试点结果的启发，即怀孕和母乳喂养都提供了保护，防止妇女感染 ADRD的发病以及在动物系统和人类中与母亲相关的神经认知益处的证据 产后神经成像研究。我们利用我们的跨学科视角。我们的项目是有成本的- 有效地利用来自NIA资助的大型队列研究的可用数据和资源。我们将分析数据 收集自参加妇女健康倡议(WHI)的7,479名65岁绝经后妇女 记忆研究(Whims)和WHI认知老化研究(WHISCA)中2,304名女性的子集。 我们还将在现有的MRI图像中对大脑萎缩进行新的测量，这些图像是从 在Whims-MRI研究中，1,403名女性的子组。我们将使用高度敏感的体素方法，即 在可视化疾病相关萎缩的次区域模式方面功能强大。目标1将考察女性历史如何 妊娠与ADRD分类、言语记忆、海马区缺血量和脑萎缩有关 测量皮质灰质厚度和皮质下灰质密度的体素方法。目标2将 检查妇女的母乳喂养史与ADRD相关病理结果的相同清单之间的关系。 这两个目标都将测试APOE-ε4载波状态的相互作用。ε4等位基因与流产有关，减少 与ε3和ε2相比，生育力和雌激素神经保护较弱，此外与 在一些人口统计群体中增加了AD风险。我们预测与怀孕和哺乳有关的 在ε4运营商中，ADRD的弹性将较弱。此外，我们怀疑生殖史可能会对 对不同形式痴呆症的致病途径的不同影响。因此，我们将进行 探索性分析按全脑缺血对队列进行分层。在这个项目之后，我们计划进行R01，以 检查内分泌、免疫、心血管和代谢生物机制，致力于临床设计 风险评估工具。该项目响应了特别关注的通知：性别和性别差异 在AD/ADRD中，征求关于生育史和特定性别的风险因素等生命过程因素的建议， 例如，怀孕。我们致力于NIA的ADRD研究实施里程碑1.i，以确定关键时期 与认知障碍和痴呆症预防有关的生活和关键生活方式以及其他参数“和 1.b“采用生命历程方法”审查“有关早期生活接触/事件的信息”。

PROJECT SUMMARY There is a critical need to understand conditions across the lifespan that may contribute to sex and gender differences in Alzheimer’s disease and related dementias (ADRD) etiologies. We focus on reproductive history, the most fundamental contributor to sex-specific health effects. Pregnancy and lactation are sensitive periods of plasticity for human mothers as well as other mammals. During these life phases, permanent, re-organizing effects transpire in various physiological systems, including the brain. Therefore, it is plausible that women’s reproductive patterns modify the risks and mechanisms involved in neuropathogenesis across the lifespan. We are galvanized by pilot results that both pregnancy and breastfeeding provided protection against women’s ADRD onset as well as evidence of motherhood-related neurocognitive benefits in animal systems and human postpartum neuroimaging studies. We capitalize on our trans-disciplinary perspective. Our project is cost- efficient in utilizing available data and resources from an NIA-funded, large cohort study. We will analyze data collected from 7,479 post-menopausal women age 65+ who participated in the Women’s Health Initiative (WHI) Memory Study (WHIMS) and from the subset of 2,304 women in the WHI Study of Cognitive Aging (WHISCA). We will also conduct new measurements of brain atrophy in existing MRI images that were collected from the subset of 1,403 women in the WHIMS-MRI study. We will use a highly sensitive, voxel-wise approach that is powerful for visualizing sub-regional patterns of disease-related atrophy. Aim 1 will examine how women’s history of pregnancy relates to ADRD classification, verbal memory, hippocampal ischemic volume, and atrophy using voxel-wise approaches to measure cortical gray matter thickness and subcortical gray matter density. Aim 2 will examine how women’s history of breastfeeding relates to the same list of ADRD-related pathology outcomes. Both aims will test the interaction of APOE-ε4 carrier status. The ε4 allele is associated with miscarriage, reduced fertility, and weaker estrogenic neuroprotection compared to ε3 and ε2, in addition to its association with enhanced AD risk in some demographic groups. We predict that pregnancy-related and breastfeeding-related ADRD resilience will be weaker in ε4 carriers. Also, we suspect reproductive history could potentially exert differential effects on etiological pathways involved in different forms of dementia. Therefore, we will conduct exploratory analyses stratifying the cohort by global ischemia. After this project, we plan to pursue an R01 to examine endocrine, immune, cardiovascular, and metabolic biomechanisms, working towards designing clinical risk assessment tools. This project is responsive to the Notice of Special Interest: Sex and Gender Differences in AD/ADRD which invites proposals on life course factors e.g., reproductive history, and sex-specific risk factors, e.g., pregnancy. We address NIA’s ADRD Research Implementation Milestones 1.I to “identify critical periods of life and critical lifestyle and other parameters with respect to cognitive impairment and dementia prevention” and 1.B to “employ a life-course approach” examining “information on early life exposures/events.”