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.”

项目概要 迫切需要了解一生中可能影响性别的条件 阿尔茨海默氏病和相关痴呆症 (ADRD) 病因学的差异 我们关注生殖史、 怀孕和哺乳期是影响特定性别健康的最根本因素。 人类母亲以及其他哺乳动物在这些生命阶段的可塑性是永久性的、重组的。 影响发生在包括大脑在内的各种生理系统中，因此，女性的影响似乎是合理的。 生殖模式改变了整个生命周期中涉及神经发病的风险和机制。 试点结果表明怀孕和母乳喂养都可以保护妇女免受感染 ADRD 的发生以及动物系统和人类中与母性相关的神经认知益处的证据 我们利用我们的跨学科视角进行产后神经影像研究。 有效利用 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 7,479 名 65 岁以上绝经后女性，她们参加了女性健康倡议 (WHI) 记忆研究 (WHIMS) 以及 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 图像中对脑萎缩进行新的测量，这些图像是从 我们将使用高度敏感的体素方法，即 WHIMS-MRI 研究中的 1,403 名女性。 目标 1 将检查女性的病史。 妊娠的影响与 ADRD 分类、言语记忆、海马缺血体积和萎缩有关 目标 2 将采用体素方法测量皮质灰质厚度和皮质下灰质密度。 研究女性的母乳喂养史与 ADRD 相关病理结果的相同列表有何关系。 这两个目标都将测试 APOE-ε4 携带者状态的相互作用 ε4 等位基因与流产、减少有关。 与 ε3 和 ε2 相比，生育能力和雌激素神经保护作用较弱，此外还与 我们预测某些人口群体的 AD 风险增加与怀孕相关和母乳喂养相关。 此外，我们怀疑生殖史可能会影响 ε4 携带者的 ADRD 恢复能力。 因此，我们将进行不同形式的痴呆症的病因学途径的不同影响。 根据全局缺血对队列进行探索性分析 在这个项目之后，我们计划进行 R01 来进行研究。 检查内分泌、免疫、心血管和代谢生物机制，致力于临床设计 该项目响应特别兴趣通知：性别和性别差异。 AD/ADRD 邀请有关生命历程因素的建议，例如生殖史和特定性别的风险因素， 例如，我们解决 NIA 的 ADRD 研究实施里程碑 1.I“确定怀孕的关键时期”。 生活和重要的生活方式以及与认知障碍和痴呆症预防有关的其他参数”和 1.B“采用生命历程方法”检查“有关早期生活暴露/事件的信息”。