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

女性的生殖生活史与阿尔茨海默病和相关痴呆症的认知能力下降和神经病理学有何关系

• 批准号: 10740751
• 负责人: Molly Maurer Fox
• 金额: $ 21.72万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-15 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10740751
• 关键词: Address; Adopted; Affect; Age; Alleles; Alzheimer' s disease related dementia; Amyloid beta-Protein Precursor; Anatomy; Animals; Anthropology; Assessment tool; Atrophic; Attenuated; Biological; Biological Markers; Biology; Birth; Brain; Breast Feeding; California; Cardiovascular system; Classification; Cognitive; Cognitive aging; Cohort Studies; Data; Data Sources; Dementia; Dependence; Detection; Disease; Elderly; Endocrine; Etiology; European ancestry; Event; Exhibits; Fertility; Funding; Genetic Polymorphism; Geriatric Psychiatry; Gravidity; Health; Hippocampus; Hormones; Human; Image; Immune; Impaired cognition; Interview; Ischemia; Lactation; Life; Life Cycle Stages; Life Style; Link; Longevity; Magnetic Resonance Imaging; Mammals; Measurement; Measures; Memory; Metabolic; Methodology; Methods; Modeling; Mothers; Neurocognitive; Neurologic; Neuropathogenesis; Neurosciences; Outcome; Participant; Pathogenesis; Pathology; Pathway interactions; Pattern; Phase; Phenotype; Physiological; Physiology; Pilot Projects; Population; Populations at Risk; Postmenopause; Postpartum Period; Pregnancy; Pregnancy Histories; Prevention; Process; Proxy; Recording of previous events; Reproductive History; Research; Resources; Risk; Risk Assessment; Risk Factors; Rodent; Role; Sample Size; Sex Differences; Spontaneous abortion; Statistical Methods; Structure; System; Testing; Thick; Time; Verbal Learning; Visualization; Woman; Women' s Health; Work; adjudication; age related; apolipoprotein E-4; carrier status; cerebral atrophy; child bearing; clinical diagnosis; clinical risk; cohort; cost efficient; critical period; dementia risk; density; design; disorder risk; early life exposure; empowerment; epidemiology study; estrogenic; experience; follow-up; gender difference; glucose metabolism; gray matter; high risk; hormone therapy; human old age (65+); improved; interest; ischemic lesion; life history; lipid metabolism; malignant breast neoplasm; men; middle age; morphometry; motherhood; neuroimaging; neuropathology; neuroprotection; novel; parity; pregnancy failure; pregnant; proband; programs; protective effect; recruit; reproductive; resilience; resilience factor; secondary analysis; sex; verbal

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.”

项目摘要 迫切需要了解整个生命周期的条件，这可能会导致性别和性别 阿尔茨海默氏病和相关痴呆症（ADRD）病因的差异。我们专注于生殖历史， 对性别特定健康影响的最基本贡献者。怀孕和泌乳是敏感的时期 人类母亲以及其他哺乳动物的可塑性。在这些生活阶段，永久性，重组 影响包括大脑在内的各种物理系统中的效果。因此，女性的合理 生殖模式改变了整个生命周期中涉及的神经病变的风险和机制。我们 被试点结果镀锌，怀孕和母乳喂养都为妇女提供了保护 ADRD发作以及与母性相关的神经认知益处的证据 产后神经影像学研究。我们利用跨学科的观点。我们的项目是成本 - 从NIA资助的大型队列研究中利用可用的数据和资源有效。我们将分析数据 从7,479名年度妇女65岁以上的妇女健康倡议（WHI）收集 在认知衰老研究中，记忆研究（WHIMS）和2,304名女性的子集​​（WHISCA）。 我们还将在现有的MRI图像中对脑萎缩进行新的测量 在WHIMS-MRI研究中，1,403名妇女的子集。我们将使用一种高度敏感的，素的方法 强大的可视化与疾病相关萎缩的次区域模式。 AIM 1将研究女性历史 与ADRD分类，言语记忆，海马缺血体积和萎缩的怀孕关系 素的方法，用于测量皮质灰质厚度和皮层灰质密度。 AIM 2意志 检查妇女的母乳喂养史与同一与ADRD相关的病理学结果列表有关。 两种目标都将测试APOE-ε4载体状态的相互作用。 ε4等位基因与流产有关，减少 与ε3和ε2相比 一些人口组中增强了AD风险。我们预测与妊娠有关和母乳喂养有关 在ε4载体中，ADRD的弹性将较弱。此外，我们怀疑复制历史可能会执行 对不同形式的痴呆症的病因学途径的差异影响。因此，我们将进行 探索性分析通过全球缺血对队列进行分层。在这个项目之后，我们计划追求R01 检查内分泌，免疫学，心血管和代谢生物力学，致力于设计临床 风险评估工具。该项目对特殊兴趣的通知有回应：性别和性别差异 在AD/ADRD中，邀请有关生活课程因素的建议，例如生殖历史和性别特定的风险因素， 例如，怀孕。我们涉及NIA的ADRD研究实施里程碑1.I，以“确定关键时期 关于认知障碍和预防痴呆症的生活和批判生活方式以及其他参数” 1.B“采用生活课程方法”检查“有关早期生活暴露/事件的信息”。